DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
INTRODUCTION
Aspect of the present application relates to process for the preparation of Modification C and mixture of Retigabine crystalline modifications and pharmaceutical compositions comprising the mixture of Retigabine crystalline modifications.
The drug compound having the adopted name “Retigabine” has a chemical name 2-amino-4-(4-fluorobenzylamino)-1-ethoxycarbonyl amino benzene and is represented by structure of formula (I).
(I)
In the United States of America, the non-proprietary name Retigabine has been superseded by ezogabine. Retigabine is a well-characterized white to slightly coloured solid and it is the active ingredient in Trobalt® (Europe) and Potiga® (US) tablets sold for the treatment of adjunctive treatment of partial onset seizures in patients aged 18 years and older.
U.S. Patent No. 5,384,330 discloses Retigabine and its pharmaceutically acceptable salts. In addition, it discloses their properties as an anti-epileptic, muscle relaxing, fever reducing, peripheral analgesic, or anti convulsive agent. U.S. Patent No. 6,538,151 discloses modification A, modification B and modification C of Retigabine and processes for the preparation thereof. Modification A was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 6.97°, 18.02°, and 19.94° 2-theta; modification B was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 15.00°, 19.29°, and 19.58° 2-theta; modification C was characterized by an X-ray powder diffraction pattern, reflections not coinciding with the reflections of the other two modifications being observed, inter alia, at 9.70° and 21.74° 2-theta.
International Application Publication No. WO 2010/105823 A1 discloses Retigabine in a non-crystalline form together with a surface stabilizer in the form of a stable intermediate and process for the preparation thereof. International Application Publication No. WO 2011/039369 A1 discloses a stable amorphous solid mixture of Retigabine and at least one pharmaceutically acceptable carrier.
International Application Publication No. WO 2013/008250 A2 discloses novel crystalline form of Retigabine designated as Form D as well as processes for the preparation of mixture of crystalline forms of Retigabine. The disclosure includes process for the preparation of mixture of crystalline modification A and crystalline modification C or mixture of crystalline modification A and crystalline modification B or mixture of crystalline modification B and crystalline modification C.
International Application Publication No. WO 2013/008250 A2 discloses a process for the preparation of mixtures of crystalline modifications of Retigabine that depends upon various parameters such as solvent, quantity of solvent, particle size of seed material, speed (rate) of addition of anti-solvent, stirring rate (rotation per minute, RPM) etc. Variation in the above mentioned parameters results in the formation of mixtures with a varied ratios.
International Application Publication No. WO 2013/179298 A2 also discloses the preparation of mixture of crystalline modifications such as mixture of crystalline modification A and modification B, mixture of crystalline modification B and modification C, and mixture of crystalline modification A and modification C.
The ratios of the individual modifications in the mixture of crystalline modifications is important and affect the formulation of the pharmaceutical dosage form. Therefore the consistent ratio of modifications is required in the mixture of crystalline modifications. The process disclosed in the prior arts involves the preparation of mixture of crystalline modifications via recrystallization from the solvents which does not provide the consistent ratio of the crystalline modifications in mixture.
The inventors of the present invention have observed that variation in the parameters may leads to the inconsistency in the formation of mixture of crystalline modifications in fixed ratio.
In view of the above, there is a need of a process for preparing mixture of crystalline modifications of Retigabine free base which provide the consistent ratio and polymorphic stability to the obtained mixture. The inventors of the present invention have developed the green process which is industrially scalable and consistently provide the crystalline mixture with desired ratio.

SUMMARY
In an aspect, the application provides a process for the preparation of modification C of Retigabine, the process comprising; slurrying the solid crystalline modifications of Retigabine in a solvent or mixture of solvent at a temperature ranging from 50° to 75°C.
In another aspect, the application provides a process for the preparation of modification C of Retigabine, the process comprising; slurrying the solid crystalline modifications of Retigabine in the mixture of ethyl acetate and cyclohexane or mixture of ethyl acetate and hexane or mixture of ethyl acetate and heptane at 50° to 75°C.
In another aspect, the application provides a process for the preparation of modification A of Retigabine, the process comprising the step of
a) dissolving Retigabine in a suitable solvent;
b) optionally, cooling the reaction mixture of step a);
c) contacting with a suitable anti-solvent and isolating crystalline modification A of Retigabine.
In another aspect, the application provides a mixture of crystalline modifications of Retigabine by physically mixing the individual crystalline modifications of Retigabine.
In another aspect, the application provides a mixture of crystalline modification A and modification C of Retigabine by physically mixing the modification A and modification C of Retigabine.
In another aspect, the application provides pharmaceutical composition comprising the mixture of crystalline modifications of Retigabine, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts a PXRD pattern of mixture of Retigabine modification A and modification C obtained according to the example-1.
Fig. 2 depicts a PXRD pattern of mixture of Retigabine modification A and modification C obtained according to the example-2.

DETAILED DESCRIPTION
In an aspect, the application provides a process for the preparation of modification C of Retigabine, the process comprising; slurrying the solid crystalline modifications of Retigabine in a solvent or mixture of solvents at a temperature ranging from 50° to 75°C.
In embodiments, the application provides a process for the preparation of modification C of Retigabine, the process comprising; slurrying the solid crystalline modifications of Retigabine in the mixture of ethyl acetate and cyclohexane or in mixture of ethyl acetate and hexane or in mixture of ethyl acetate and heptane at a temperature ranging from 50° to 75°C.
In embodiments, the solvent which may be used for making the slurry includes but are not limited to mixture of ethyl acetate and cyclohexane or mixture of ethyl acetate and hexane or mixture of ethyl acetate and heptane or any other suitable combinations of solvents.
In embodiments, the single solvent can also be used for making the slurry and getting modification C of Retigabine. In embodiments, the single solvent which may be used for the preparation of modification C of Retigabine includes but are not limited to solvents such as Ethyl acetate, Isopropyl alcohol, chlorobenzene, cyclopentyl methyl ether etc or any other suitable solvent.
In embodiments, the solid crystalline modification which can be used as a starting material for the preparation of modification C can be modification A or modification B or mixture of modifications as described in the present application, or any other crystalline forms/modifications known in the literature.
In embodiments, the slurry obtained can be maintained at 50°C to 75°C for 10 minutes to 10 hours or longer.
In embodiments, the crystalline modification C of Retigabine can be isolated by the using the techniques known in the art such as filtration. The obtained crystalline modification C of Retigabine can be dried at suitable temperature for sufficient time.
In another aspect, the application provides a process for the preparation of modification A of Retigabine, the process comprising the step of
d) dissolving Retigabine in a suitable solvent;
e) optionally, cooling the reaction mixture of step a);
f) contacting with a suitable anti-solvent and isolating crystalline modification A of Retigabine.
In embodiments, the solid crystalline modification which can be used as a starting material for the preparation of modification A can be modification B or modification C or mixture of modifications as described in the present application, or any other crystalline forms/modifications known in the literature.
In embodiments, step a) may be carried out by dissolving Retigabine at a suitable temperature of about 25°C to boiling point of the solvent. In embodiments, the clear solution of step a) may be optionally filtered to make it particle free.
In embodiments, step b) may be carried out by cooling the reaction mass of step a) to a suitable temperature of about 0°C to 20°C.
In embodiments, step c) may be carried out by adding suitable anti-solvent to the reaction mass of step a) or b) or by adding reaction mass of step a) or b) to anti-solvent. In embodiments, addition may be carried out in multiple lots or in single lot.
In embodiments, suitable solvent of step a) may be ethyl acetate or the like and suitable anti-solvent of step c) may be cyclohexane or the like.
In embodiments, step c) may be carried out for time sufficient to isolate crystalline modification A. In embodiments, step c) may be carried out at a suitable temperature of about 0°C to 20°C.
In embodiments, the crystalline modification A of Retigabine can be isolated by the using the techniques known in the art such as filtration. The obtained crystalline modification A of Retigabine can be dried at suitable temperature for sufficient time.
In another aspect, the application provides a mixture of crystalline modifications of Retigabine by physically mixing the individual crystalline modifications of Retigabine.
Mixture of crystalline modifications of Retigabine may be a mixture of modification A and modification B; or a mixture of modification A and modification C; or a mixture of modification B and modification C; or a mixture of modification A, modification B and modification C; or a mixture of one or more of modifications A, B, or C with any other polymorph.
The mixture of crystalline modifications of Retigabine as used here contains from about 1% to about 99% by weight of a particular polymorph and from about 99 % to about 1% by weight of one or more of any other polymorphs.
In another aspect, the application provides a mixture of crystalline modification A and modification C of Retigabine by physically mixing the modification A and modification C of Retigabine.
The mixture of Retigabine modification A and modification C as described herein contains from about 1% to about 99% by weight of modification A or about 1% to about 99% by weight of modification C. According to one embodiment, the mixture of Retigabine modification A and modification C as described herein contains from about 10% to about 90% by weight of modification A or about 10% to about 90% by weight of modification C. According to one embodiment, the mixture of Retigabine modification A and modification C as described herein contains from about 20% to about 80% by weight of modification A or about 20% to about 80% by weight of modification C. According to the further embodiment, the mixture of Retigabine modification A and modification C as described herein contains from about 30% to about 70% by weight of modification A or about 30% to about 70% by weight of modification C. According to the further embodiment, the mixture of Retigabine modification A and modification C as described herein contains from about 40% to about 60% by weight of modification A or about 40% to about 60% by weight of modification C. According to the further embodiment, the mixture of Retigabine modification A and modification C as described herein contains from 50% by weight of modification A and 50% by weight of modification C.
In embodiments, the physical mixing of crystalline modifications can be performed at any suitable temperature. Preferably, the physical mixing of crystalline modifications can be performed at a temperature at about 10 to 40°C. In embodiments, optionally the physical mixing of crystalline modifications can be performed in the presence of an inert atmosphere.
In embodiments, the physical mixing of crystalline modifications can be performed in equipment suitable for mixing such as mixer, blender etc. or any other suitable equipment that may be useful for mixing.
In embodiments, the crystalline modification A and crystalline modification C may be characterized by X-ray powder diffraction pattern as depicted in Fig.1.
In embodiments, the mixture of crystalline modification A and crystalline modification C may be characterized by X-ray powder diffraction pattern having peaks at about 5.0°, 7.0°, 9.7°, 18.0°, 19.9°, 21.8°, 28.4°±0.2° 2?.
In embodiments, the crystalline mixtures of Retigabine modifications as described in the present application are stable. In embodiments, the mixture of crystalline modification A and modification C of Retigabine is stable with respect to the chemical purity as well as polymorph purity after storage for at least 3 months (i) at 40°C and a relative humidity of 75% or (ii) at 25°C and a relative humidity of 60%.

Test Stability at 40°±2°C/RH 75± 5%
Initial After 1 month After 2 months After 3 months
Polymorph by PXRD Crystalline
(Mixture of A+C) No change No change No change
Chemical purity by HPLC 99.91% 99.95% 99.92% 99.96%

In embodiments, the crystalline mixtures of Retigabine modifications as described in the present application are stable even in the absence of any inert atmosphere. Inert atmosphere includes, but not limited to an oxygen scavenger, under vacuum or in presence of an inert gas such as nitrogen. In embodiments, the mixture of crystalline modification A and modification C of Retigabine is stable in the absence of any inert atmosphere with respect to the chemical purity as well as polymorph purity at all ICH specified storage conditions.
In embodiments, the crystalline mixtures of Retigabine modifications as described in the present application are packed in clear polyethylene bag with a tag/plastic strip by twisting after removing the air as for as possible. Keep this clear polyethylene bag in black polyethylene bag and tie it properly with tag/plastic strip by twisting after removing the air as far as possible. Keep it in a triple laminated bag and seal it with four liner sealer and keep it in a HDPE container. Store this at 25°C (excursions allowed between 15 to 30°C)
In embodiments, the starting material (Retigabine) that can be used in any aspect of the present application may be prepared according to any of the procedures known in literature or according to the methods described in the present application.
Retigabine can be prepared according to any of the methods of scheme-I to scheme -III as following.

Scheme-I involves the reaction of 4-fluorobenzaldehyde with 2-nitro-p-phenylenediamine to form imine intermediate (Ia) followed by its reduction in the presence of a catalyst such as sodium borohydride, sodium cyanoborohydride or Sodium triacetoxyborohydride to produce nitro intermediate (Ib). This nitro intermediate upon hydrogenation in the presence of a catalyst like Raney Nickel, palladium on carbon or platinum produces amine intermediate (Ic) which on subsequent reaction with ethyl chloro formate produces Retigabine.

Scheme-II involves the protection of amino group in N-ethoxycarbonyl-p-phenylenediamine with phthalic anhydride followed by nitration using nitrating agents like nitric acid and glacial acetic acid or nitric acid and sulfuric acid to give 2-ethoxycarbonylamino-5-phthalimido-nitrobenzene (IIb). This intermediate upon deprotection, followed by reaction with 4-fluorobenzaldehyde produces nitro intermediate (II d) which on further hydrogenation in the presence of a catalyst like Raney Nickel, palladium on carbon or platinum produces Retigabine.

Scheme-III involves the reaction of 2, 4-dinitro aniline with ethyl chloroformate in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, dimethyl amino pyridine, diisopropyl ethyl amine to obtain N-ethoxycarbonyl 2, 4-dinitro aniline (IIIa). This intermediate is reduced to corresponding N-ethoxycarbonyl 2,4-diamino aniline (IIIb) in presence of a suitable catalyst such as Raney Nickel, palladium on carbon or Platinum and condensed with 4-fluorobenzaldehyde in presence of a base such as triethylamine, diisopropyl ethyl amine, titanium isopropoxide to form corresponding imine intermediate (IIIc) followed by reduction in the presence of a catalyst such as sodium borohydride, sodium cyanoborohydride or Sodium triacetoxyborohydride to produce Retigabine.
The mixture of crystalline modifications of Retigabine obtained according to the process of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.
In embodiments, the individual crystalline modifications of Retigabine can be micronized to get the desired particle size before or after the physical mixing to obtain the mixture of crystalline modifications of Retigabine in the desired particle size.
In embodiments, any crystalline modification of Retigabine according to the present application has a particle size distribution wherein: d(0.1) is less than about 50 µm or less than about 25 µm; or less than about 15 µm; d(0.5) is less than about 100 µm or less than about 50 µm; and d(0.9) is less than about 250 µm or less than about 200 µm or less than about 150 µm.
In embodiments, mixture of crystalline modifications of Retigabine according to the present application has a particle size distribution wherein: d(0.1) is less than about 50 µm or less than about 25 µm; or less than about 15 µm; d(0.5) is less than about 100 µm or less than about 50 µm; and d(0.9) is less than about 250 µm or less than about 200 µm or less than about 150 µm.
In embodiments, the crystalline modification A, modification B, modification C used in the present application for making mixture of modifications can be prepared by the procedures known in the literature or according the processes as described in the present application.
In embodiments, the mixture of crystalline modifications of Retigabine obtained by a method of the present application having a chemical purity greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).
In embodiments, the mixture of crystalline modifications of Retigabine obtained by the method of the present application as described herein has total impurities including the starting material less than 0.5% as determined using high performance liquid chromatography (HPLC). In embodiments, the mixture of crystalline modifications of Retigabine obtained by a method of the present application as described herein has total impurities including the starting material less than 0.1% as determined using high performance liquid chromatography (HPLC). In embodiments, the impurities which may present in Retigabine such as starting materials, intermediates and probable impurities such as 2, 4-dinitroaniline, 2, 4-dinitrochlorobenzene, bis(2,4-dinitrophenyl)amine, ethyl (2,4-dinitrophenyl) carbamate, ethyl (2-amino-4-nitrophenyl)carbamate, ethyl(4-amino-2-nitrophenyl)carbamate,ethyl(2,4-diaminophenyl) carbamate, ethyl (2,4-bis((4-fluorobenzyl)amino)phenyl)carbamate, ethyl (2-amino-4-(benzylamino)phenyl)carbamate, ethyl (2-amino-4-((3-fluoro benzyl)amino)phenyl)carbamate, diethyl (4,4',6,6'-tetraamino-[1,1'-biphenyl]-3,3'-diyl)dicarbamate, diethyl (2,2',6,6'-tetraamino-[1,1'-biphenyl]-3,3'-diyl)dicarbamate, 4-fluorobenzylchloride, 4-fluorobenzalchloride etc.
In embodiments, Retigabine obtained according to the process of the present invention may contain less than 0.5% of the impurities mentioned herein or less than 0.1% of the impurities mentioned herein or less than 0.05% of the impurities mentioned herein or less than the limit of detection or less than limit of quantification of the impurities mentioned herein. In embodiments, Retigabine obtained according to the process of the present invention contains the impurity profile (content of impurities) same or less than that of the innovator tablet when analyzed.
In embodiments, 4-fluorobenzaldehyde is used as one of the starting material in most of the synthetic processes available in the literature for the preparation of Retigabine. 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, benzaldehyde are the possible impurities that may present in 4-fluorobenzaldehyde. These impurities, if present may lead to the formation of corresponding impurities at the intermediate stages and at the final product. Therefore, the starting material 4-fluorobenzaldehyde can be purified to remove the isomeric impurities as mentioned above or any other impurities before using in the synthesis of Retigabine so that the final product can be obtained with desired purity which can be directly used in the pharmaceutical preparation without any further purification of API. The purification of 4-fluorobenzaldehyde can be done by fractional distillation or any other methods known in the art.
In embodiments, the process described in the present application or the process described in WO 2013/008250 A2 are also capable of removing the isomeric impurities of 4-fluorobenzaldehyde or the impurities formed at intermediate stage or at the final stage.
In embodiments, the ratio of the individual crystalline modifications of Retigabine in the mixture of modifications can be determined by using the known technique such as, X-ray powder diffraction (XRPD), Infrared spectroscopy (IR), Differential scanning calorimetry (DSC), Raman spectroscopy etc. The quantification result i.e., ratio of the mixture of crystalline modifications may vary depending upon the analytical technique used and sensitivity of the method and instrument.
X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 5.0°" means "having a diffraction peak at a diffraction angle (2?) of 4.8° to 5.2°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks can vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors can slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).
The PXRD pattern of the mixture of modification A and modification C of Retigabine may vary in terms of intensities in view of the variation in the ratio of the mixture.
An aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of Retigabine, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions comprising Retigabine of the application together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
DEFINITIONS
The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise.
The terms modification, polymorph and crystalline form are used interchangeably herein.
The term physical mixing used herein means, taking two substances separately and then mixing both the substance to obtain a composition. The mixing may be performed by using suitable equipment such as mixer, blender or any other suitable equipment.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example 1: Preparation of mixture of Retigabine modification A and modification C by physical mixing.
Retigabine modification A (15 g) and modification C (15 g) were charged into a Buchi rotavapour flask at 30°C. The flask containing the modification A and modification C was kept under rotation without vacuum for 30 minutes. The obtained product was sieved using 30 mesh size sieve to get the mixture of crystalline Retigabine modification A and modification C. Yield: 29 g, HPLC purity: 99.87%.
D (0.1) = 7.33 µm, D (0.5) = 35.53 µm, D (0.9) = 120.07 µm.
The obtained product contains 49.6% (w/w) of modification A and 50.4% (w/w) of modification C determined by using NIR technique.
Example 2: Preparation of mixture of Retigabine modification A and modification C by physical mixing.
Retigabine modification A (20 g) and modification C (20 g) were charged into a Buchi rotavapour flask at 30°C. The flask containing the modification A and modification C was kept under rotation without vacuum for 1 hour. The obtained product was sieved using 60 mesh size sieve to get the mixture of crystalline Retigabine modification A and modification C. Yield: 35.2 g, HPLC purity: 99.92%
D (0.1) = 8.2 µm, D (0.5) = 38.43 µm, D (0.9) = 125.6 µm.
The obtained product ratio was determined by using NIR technique.
Example 3: Preparation of Retigabine modification C.
Retigabine modification A (10 g), ethyl acetate (10 mL) and cyclohexane (40 mL) were charged into a flask at 30°C. The obtained slurry was heated to 70°C under stirring and maintained for 5 hours at 70°C. The slurry was filtered at 70°C and washed with cyclohexane (20 mL). The obtained product was dried under vacuum at 30°C for 9 hours. Yield: 9.1 g. HPLC purity: 99.91%,
D(0.1) = 7.70 µm, D(0.5) = 28.17 µm, D(0.9) = 69.77 µm.
Example 4: Preparation of Retigabine modification C.
Retigabine modification A (5 g), ethyl acetate (10 mL) and heptane (40 mL) were charged into a flask at 30°C. The obtained slurry was heated to 63°C under stirring and maintained for 4 hours 30 minutes at 63°C. The slurry was filtered at 63°C and washed with n-heptane (10 mL). The obtained product was dried under vacuum at 30°C for 8 hours. Yield: 4.3 g.
Example 5: Preparation of Retigabine modification C.
Retigabine modification B (5 g), ethyl acetate (5 mL) and cyclohexane (2 mL) were charged into a flask at 30°C. The obtained slurry was heated to 62°C under stirring and maintained for 1 hour 30 minutes at 62°C. The slurry was filtered at 62°C to obtain the modification C of Retigabine.
Example 6: Preparation of Retigabine modification C.
Retigabine modification A (10 g), cyclopentyl methyl ether (50 mL) were charged into a flask at 30°C. The obtained slurry was heated to 62°C under stirring and maintained for 5 hours at 62°C. The slurry was filtered at 62°C and washed with cyclopentyl methyl ether (20 mL). The obtained product was dried under vacuum at 30°C. Yield: 6.9 g.
Example 7: Preparation of Retigabine modification C.
Retigabine modification A (5 g), chlorobenzene (15 mL) were charged into a flask at 28°C. The obtained slurry was heated to 61°C under stirring and maintained for 1 hour at 61°C. The slurry was filtered at 61°C and washed with chlorobenzene (5 mL). The obtained product was dried under suction at 30°C. Yield: 3.2 g.
Example 8: Preparation of Retigabine modification A.
Retigabine (10 g) and ethyl acetate (80 mL) were charged into a flask at 28°C. The reaction mass was heated to 43°C and stirred to get a solution. Water (100 mL) was added to the reaction mass 43°C and stirred for 45 minutes. The layers were separated and the organic layer was washed with water (100 mL). The organic layer was charged into a flask at 43°C and cooled to 28°C under stirring and further cooled to 18°C and Cyclohexane (90 mL) was added to the flask at 18°C. The precipitated slurry was further cooled to 2°C and maintained for 30 minutes. The precipitated product was collected by filtration and washed with cyclohexane (20 mL). The obtained product was dried under vacuum at 28°C for 3 hours. Yield: 8.9 g. HPLC purity: 99.89%.
Example 9: Preparation of Retigabine modification A.
Retigabine (40 g) and ethyl acetate (320 mL) were charged into a flask at 27°C. The reaction mass was heated to 55°C and stirred to get a solution. Hot solution was filtered at the same temperature to make it particle free solution and the filter was washed with ethyl acetate (40 mL). Reaction mass was cooled to 24°C and cyclohexane (480 mL) was added. Further cooled the reaction mass to -4°C and stirred at the same temperature for an hour. Solid was filtered and washed with cyclohexane (40 mL). Wet compound was dried under vacuum at 35°C for 2.5 hours to obtain the title compound. Yield: 37.1 g. HPLC purity: 99.92%
Example 10: Preparation of Retigabine modification C.
Retigabine modification A (30 g) was charged to a mixture of ethyl acetate (27 mL) and cyclohexane (153 mL) in a flask at 26°C. The obtained slurry was heated to 67°C under stirring and maintained for 2 hour at 67°C. The slurry was filtered at 67°C and washed with cyclohexane (60 mL). Wet solid was dried under vacuum at 30°C for 2.5 hours to obtain the title compound. Yield: 28.7 g. HPLC purity: 99.90%
,CLAIMS:We Claim:
1. A process for the preparation of crystalline modification C of Retigabine comprising the step of slurrying Retigabine in a suitable solvent or mixture of solvents at about 50°C to 75°C.

2. A process of claim 1, wherein the suitable solvent is selected from Ethyl acetate, Isopropyl alcohol, chlorobenzene and cyclopentyl methyl ether.

3. A process of claim 1, wherein the mixture of solvents are selected from mixture of ethyl acetate and cyclohexane; mixture of ethyl acetate and hexane; and mixture of ethyl acetate and heptane.

4. A process for the preparation of crystalline modification A of Retigabine comprising the step of
a) dissolving Retigabine in a suitable solvent;
b) optionally, cooling the reaction mixture of step a);
c) contacting with a suitable anti-solvent and isolating crystalline modification A of Retigabine.

5. A process of claim 4, wherein the suitable solvent is ethyl acetate.

6. A process of claim 4, wherein the suitable anti-solvent is cyclohexane.

7. A mixture of crystalline modifications of Retigabine obtained by physically mixing the individual crystalline modifications of Retigabine.

8. A mixture of claim 7, wherein the individual crystalline modifications of Retigabine are modification A and modification C.
9. A mixture of claim 8, wherein it contains about 30% to about 70% by weight of modification A or modification C.

10. A pharmaceutical composition comprising the mixture of crystalline modifications of Retigabine of claim 7 to claim 9 and one or more pharmaceutically acceptable excipients.