FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: NOVEL POLYMORPH OF RETIGABINE
DIHYDROCHLORIDE OF FORMULA I AND PROCESS FOR THEIR
PREPARATION.
2. APPLICANT:
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH HOUSE, 541-A,
MAROL- MAROSHI ROAD, MUMBAI, 400059, INDIA
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: Novel polymorph of retigabine dihydrochloride of formula I and process for preparation.
FIELD OF TECHNOLOGY:
The present invention relates to solid crystalline polymorphs of retigabine dihydrochloride of formula I. The invention further relates to methods for producing retigabine dihydrochloride in said solid crystalline polymorphic forms. The crystalline forms of retigabine dihydrochloride disclosed herein can be used for the preparation of pharmaceutical composition for the purpose of treatment of partial epilepsies muscle relaxing, fever-reducing, convulsions and other disorders those are cured with retigabine and its pharmaceutically acceptable salts particularly dihydrochloride.

BACKGROUND OF THE INVENTION:
Retigabine (INN) or Ezogabine (USAN), code named D-23129, is an anticonvulsant for the treatment for partial epilepsies and also for muscle relaxing, fever-reducing and as peripheral analgesic agent. The drug is being developed by Valeant Pharmaceuticals and Glaxo SmithKline with the proposed trade name Potiga. The FDA Peripheral and Central Nervous System Drugs Advisory Committee have unanimously recommended approval of Potiga. The ability of Retigabine to open potassium channels in neuronal cells differentiates from presently available anticonvulsant agents such as Phenytoin, Carbamazepine and Valproate. European Commission has granted the marketing authorization for Trobalt™ (retigabine) in the epilepsy therapy area. U.S Food and Drug Administration (FDA) has approved as Potiga (ezogabine).The drug is known as ezogabine in the US and Canada. The encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal

hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favour action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, anti-epileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. In the mid 1980's, under the auspices of the NIH Antiepileptic Drug Development Program, flupirtine was also shown to have anticonvulsant effects in animal models of epilepsy and in patients with refractory seizures. The most potent of these derivatives was D-20443, the dihydrochloride salt of retigabine, which was subsequently developed as a free base due to technological reasons and superior impurity profile
Retigabine works primarily as a potassium channel opener that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain.
CNS Drug Reviews 2005, 11(1), 1-20 discloses that retigabine dihydrochloride is hygroscopic and during medium to long-term storage at (-) 18°C (with presumed freeze-drawing) produces significant amounts of the ring-closed product 5-(4-fluorobenzylamino)-l,3-dihydro-benzimidazol-2-one and small amounts of uncharacterized oxidized products. Therefore, it is preferably stored as the free base, isolated from light.
The compound of formula I and its preparation is disclosed in DE4200259.
US5914425 (Meisel et al.) discloses homogeneous crystalline forms A, B and C of 2-amino-4-(4-fluorobenzylamino)-l-ethoxycarbonylaminobenzene of formula (II) hereinabove and herein—below referred as retigabine base, which meets the pharmaceutical requirements. The solid crystalline forms A, B and C are also referred as modifications A, B and C.


The said '425 patent does not disclose nor gives any indication about the possibility or existence of polymorphic form of retigabine dihydrochloride of formula I.
US 5849789 and US5852053 (both of Rostock et al.) disclose the use of retigabine for the treatment of neurodegenerative disorders, including those associated with stroke.
WO2011/012659A2 (Medichem S.A.) discloses diethyl-4-(4-fluorobenzylamino)-1,2-phenylenedicarbamate and salts thereof of the formula given below, which are useful as reference markers and reference standards for analyzing samples comprising retigabine or salts thereof.

Diethyl-4-(4-fluorobenzylamino)-l,2-phenyIenedicarbamate
US5384330 (Dieter et al.) discloses 1,2,4-triaminobenzene derivatives of the general formula:


and pharmaceutically acceptable acid addition salts thereof and their properties as anti-epileptic, muscle-relaxing, fever-reducing and peripheral analgesic agents.
WO2010105823/ US2012053238 (Al) discloses a process for the preparation of non-crystalline retigabine comprising dissolving retigabine and surface stabilizer in a solvent or solvent mixture, and spraying the solution on a carrier core, or spray drying or freeze-drying the solution; mixing retigabine and surface stabilizer, and extruding the mixture, where the extrusion conditions are selected in such a manner that a transition from crystalline to non-crystalline retigabine takes place; or mixing retigabine and surface stabilizer, and grinding the mixture, where the grinding conditions are selected in such a manner that a transition from crystalline to amorphous retigabine takes place. The invention relates to solid retigabine in non-crystalline form together with a surface stabilizer in the form of a stable intermediate.
Centre for drug evaluation and Research, Chemistry reviews an application number 022345Origls000 which discloses that retigabine base is practically insoluble (0.04 to 0.05 mg/mL) in water or aqueous media above pH 5 and sparingly soluble (16 mg/mL) in 0.1 N HC1. It has a pKa of 3.7. The drug substance is non-hygroscopic. This brings a great limitation in the bioavailability of retigabine base as a drug substance and drug product thereof.
None of the prior arts cited hereinabove discloses any polymorphic form of retigabine dihydrochloride.
US5914425 filed fourteen years ago, makes no reference to the existence of specific polymorphic forms of retigabine dihydrochloride. However,'425 discloses a process comprising crystallization of retigabine dihydrochloride using ethanol as solvent and the said material obtained has neither been assigned any specific polymorphic form nor characterized. The inventors of the present invention have obtained the crystalline retigabine dihydrochloride based on the process disclosed therein in '425 and have characterized the said crystalline form as Form-II and the same is referred as inherent polymorphic form of patent '425 hereinabove and hereinbelow. However, disclosed herein is a novel stable polymorphic form designated as Form-I obtained by using methanol (Q alcohol) as a solvent. The

novel polymorphic form I of the present invention differs in its morphology from the inherent polymorphic Form-II obtained from C2 and C3 alcoholic solvents. Different crystalline polymorphs of a drug substance may have different physical and chemical properties such as melting point, hygroscopicity, stability, solubility and/or dissolution rate, bulk density, crystallinity, crystal habits, bioavailability, chemical reactivity and formulation handling characteristics, which are among the numerous properties that need to be considered for preparing the medicament that can be effectively administered. Therefore, regulatory agencies require a definitive control of polymorphic form of the active component in medicaments particularly in solid pharmaceutical dosage forms.
Accordingly there is a dire need to study new polymorphic forms of retigabine dihydrochloride that will have good thermal stability, material flow characteristics, lower water contents that offers advantages for preparing reproducible pharmaceutical formulations. The inventors of the instant invention; therefore, disclose herein polymorphs of retigabine dihydrochloride, having better solubility in water responsible for better bio-availability when compared with that of retigabine base.
Disclosed herein is a novel stable crystalline polymorphic form designated as form I of retigabine dihydrochloride which can be used as medicine as an anticonvulsant for the treatment for partial epilepsies and also for muscle relaxing, fever-reducing and as peripheral analgesic agent.
OBJECT OF THE INVENTION:
Disclosed herein is stable novel crystalline form of retigabine dihydrochloride having better solubility in water compared to retigabine base, stable, non-hygroscopic, better flow able property and the said novel polymorphic form can be used for the development of formulation product.
Also disclosed herein is the characterization and designation of the crystalline form of the retigabine dihydrochloride obtained by the process disclosed therein in '425 and designation of the said inherent polymorphic material as form-II.

First aspect of the invention is to provide stable novel crystalline form I of retigabine dihydrochloride characterized X-ray diffraction pattern as shown in figure I, comprising 29 values at 5.89, 11.81, 12.78, 13.13, 13.74, 15.05, 15.40,
16.37, 16.91, 17.37, 17.78, 19.01, 19.62, 21.40, 22.03, 22.50, 23.41, 23.78, 24.23,
24.81, 25.26, 26.26, 26.64, 26.99,27.73, 28.18, 28.49, 29.28, 29.85, 32.07, 32.42,
32.75, 33.61, 33.90, 34.38, 35.25, 36.00, 36.65, 37.38, 37.79, 38.47 (±0.2°, 29).
Second aspect of the invention is to provide novel crystalline form I of retigabine dihydrochloride further characterized by 29 values at 11.81, 17.78, 19.01, 19.62, 21.40, 22.03, 23.78, 29.85 (±0.2°, 20).
Third aspect of the invention is to provide novel crystalline form I of retigabine dihydrochloride further characterized by relative intensity in the range of 10 to 100%.
Fourth aspect of the invention is to provide novel crystalline form I of retigabine dihydrochloride further characterized by its non-linear shape e.g. bi-pyramidal shaped crystals as indicated in figure II.
Fifth aspect of the invention is to provide the process for the preparation of novel crystalline form I of retigabine dihydrochloride.
Sixth aspect of the invention is to designate inherent crystalline solid product of retigabine dihydrochloride as form-II and characterized by X-ray diffraction pattern as shown in figure III, comprising 29 values at 5.74, 8.35, 10.71, 11.39, 12.24, 13.51, 16.06, 16.45, 16.91, 17.64, 18.20, 19.31, 20.26, 20.54, 21.11, 21.72,
22.38, 22.92, 23.37, 23.73, 24.32, 25.03, 26.08, 26.80, 27.23, 28.31, 29.00, 29.39,
30.40, 31.44, 32.24, 32.81, 33.53, 33.87, 34.94, 35.78, 36.69, 36.90, 37.66, 39.17
(±0.2°, 29).
Seventh aspect of the invention is to characterize inherent crystalline form II of retigabine dihydrochloride by 29 values at 11.39, 12.24, 13.51, 18.20, 21.11, 21.72, 22.92, 24.32, 26.08, 26.80, 29.39, and 32.81 (±0.2°, 20).

Eighth aspect of the invention is to characterize inherent crystalline form II of retigabine dihydrochloride by relative intensity in the range of 10 to 100%.
Ninth aspect of the invention is to characterize inherent crystalline form II of retigabine dihydrochloride by its linear shape e.g. needle shaped crystals as indicated in figure IV.
Tenth aspect of the invention is to provide novel process for the preparation of inherent crystalline form II of retigabine dihydrochloride.
SUMMARY OF THE INVENTION:
Disclosed herein are two crystalline polymorphic forms viz novel stable form referred as form I and inherent form of patent '425 referred as form-II characterized by their 20 values and their crystal shapes. When retigabine dihydrochloride is crystallized comprising using methanol or methanolic hydrochloride novel polymorphic form-I is obtained which is found to be nonlinear e.g. bi-pyramidal shape as illustrated in figure II. The inventors of the present invention have also discovered that form-I is formed when acetonitrile, acetone and mixture thereof is used as an anti-solvent for the crystalisation of retigabine dihydrochloride soluble in water. On the other hand when retigabine dihydrochloride is crystallized using ethanol or ethanolic HC1 as a solvent as disclosed in patent '425 then inherent crystalline form-II is obtained which has needle shaped crystals as illustrated in figure IV. The inventors of the present invention have also discovered that same inherent form-II is formed when isopropanol or isopropanol -HC1 mixture is used as a solvent for the crystalisation of retigabine dihydrochloride.
DESCRIPTION OF THE FIGURES:
Figure I represents X-ray diffractogram of form I.
Figure II represents non-linear e.g. bi-pyramidal shape of form I.
Figure III represents X-ray diffractogram of form II.
Figure IV represents linear e.g. needle shaped of form II.

DETAILED DESCREPTION OF THE PRESENT INVENTION:
It has been observed that the novel crystalline form of retigabine dihydrochloride, form-I disclosed herein, is as stable as inherent form-II and it does convert neither spontaneously nor during storage into inherent form-II of patent'425. The Figure V represents initial chemical purity of retigabine dihydrochloride novel polymorphic form-I while figure VI represents chemical purity of retigabine dihydrochloride novel polymorphic form-I after storage for about four months at laboratory conditions. The results indicate that novel polymorphic form-I of retigabine dihydrochloride has better shelf life when stored under proper conditions. Furthermore, retigabine dihydrochloride form-I is more impact (tapped Bulk Density 0.45 gms/cc) than inherent form-II (tapped bulk density 0.36 gm/cc), therefore, less electrostatic than inheriant form-II and may hence be more readily subjected to any treatment under the standard usual conditions of pharmaceutical technology particularly during formulation at industrial scale.



Inventors of the instant invention have observed that polymorphs of retigabine dihydrochloride isolated from methanol and C2-C3 alcohols have different characteristics, therefore, different polymorphic forms.
Disclosed herein are two polymorphs of retigabine dihydrochloride represented by form I and form II illustrated in figures I and III respectively. Microscopic study reveals that crystal of form I of the present invention is non-linear and it is found to be bi-pyramidal in shape as illustrated in figure II herein above. Inherent form II from patent '425 is linear and found to be needle shaped as illustrated in figure IV.
Disclosed herein are the processes for the preparation of novel polymorphic form I as described hereinbelow:
1. Retigabine base dissolved in methanol is treated either with methanolic hydrochloride or is purged with hydrogen chloride gas to obtain novel polymorphic form I of retigabine dihydrochloride.
2. Inherent form II of retigabine dihydrochloride is dissolved in water and then contacted with nitrile solvent to obtain novel polymorphic form I of retigabine dihydrochloride.
3. Inherent form II is dissolved in water and then contacted with ketonic solvent
to obtain novel polymorphic form I of retigabine dihydrochloride.

Nitrile solvent used hereinabove for the preparation of novel polymorphic form I of retigabine dihydrochloride is selected from the group comprising C2-C5 nitriles. Preferably nitrile solvent is acetonitrile.
Ketonic solvent used herein above for the preparation of novel polymorphic form I of retigabine dihydrochloride is selected from the group comprising C3-C8 ketones and the like. Preferably ketonic solvent is acetone.
Form II is prepared by the process comprising dissolving retigabine base in aliphatic alcohol other than methanol and contacting the said mass with alcoholic hydrogen chloride or by purging hydrogen chloride gas.
The aliphatic alcohols used herein above for the preparation of inherent form II is selected from the group comprising C2-C6 linear or branched alcohols and mixture thereof. Preferably aliphatic alcohol is selected from ethanol, isopropanol and mixture thereof
Novel polymorphic form I of retigabine dihydrochloride is characterized by its 29 values as 5.89, 11.81, 12.78, 13.13, 13.74, 15.05, 15.40, 16.37, 16.91, 17.37, 17.78, 19.01, 19.62, 21.40, 22.03, 22.50, 23.41, 23.78, 24.23, 24.81, 25.26, 26.26, 26.64, 26.99, 27.73, 28.18, 28.49, 29.28, 29.85, 32.07, 32.42, 32.75, 33.61, 33.90, 34.38, 35.25, 36.00, 36.65, 37.38, 37.79, 38.47 (±0.2°, 20).
Inherent polymorphic Form II of retigabine dihydrochloride is characterized by its 26 values as 5.74, 8.35, 10.71, 11.39, 12.24, 13.51, 16.06, 16.45, 16.91, 17.64, 18.20, 19.31, 20.26, 20.54, 21.11, 21.72, 22.38, 22.92, 23.37, 23.73, 24.32, 25.03, 26.08, 26.80, 27.23, 28.31, 29.00, 29.39, 30.40, 31.44, 32.24, 32.81, 33.53, 33.87, 34.94, 35.78, 36.69, 36.90, 37.66, 39.17 (±0.2°, 20).
The invention can be best understood by the following non limiting examples given hereinbelow:

EXAMPLE-1: Preparation of retigabine dihydrochloride form-L
Experiment-1: Retigabine base (22 g) is taken in methanol (264 ml) and stirred for 20-30 minutes at RT. Then methanolic-HCl (23% w/w) is added slowly through addition funnel in 20-30 minutes. The reaction mass is stirred to 25-30°C in 2 hours. Solid appeared is filtered, washed with methanol and dried under vacuum at 40-45°C to get retigabine dihydrochloride (25.0 g) form-I as off-white crystalline material.
Experiment-2: Retigabine dihydrochloride form-II (2 g) is taken in DM water (20 ml) and stirred at RT for 20-30 minutes to get the clear solution. Then acetonitrile (20 ml) is added slowly through addition funnel in 10 minutes. The reaction mass is then distilled-off at 40-45°C under vacuum to half of its original volume and again heated to 55-60°C to get the clear solution. Then reaction mass is slowly allowed to cool to RT. The solid appeared is filtered, washed with acetonitrile and dried under vacuum at 40-45°C to get the off-white crystalline form-I of retigabine dihydrochloride.
Experiment-3: Retigabine dihydrochloride form-II (2 g) is taken in DM water (20 ml) and stirred at RT for 20-30 minutes to get the clear solution. Then acetone (20 ml) is added slowly through addition funnel in 10 minutes. Then distilled -off the reaction mass at 40-45°C under vacuum to half of its original volume and again heated the reaction mass to 45-50°C to get the clear solution. Then reaction mass is slowly allowed to cool to RT. The solid appeared is filtered, washed with acetone and dried under vacuum at 40-45°C to get the off-white crystalline form-I of retigabine dihydrochloride.
EXAMPLE-2: Preparation of retigabine dihydrochloride form-II.
Experiment-4: Retigabine base (15 g) is taken in ethanol (180 ml) and stirred for 20-30 minutes at RT. Then ethanolic-HCl (27% w/w) is added slowly through addition funnel in 20-30 minutes. Reaction mass is cooled to 25-30°C and further stirred for 1 hour at 25-30°C. Solid appeared is filtered, washed with ethanol (15 ml) and dried under vacuum at 40-45°C to get the retigabine dihydrochloride (14.8 g) form-II as off-white crystalline material.

Experiment-5: Retigabine base (12 g) is taken in isopropyl alcohol (120 ml) and stirred for 20-30 minutes at RT. Then IPA-HC1 (16% w/w) is added slowly through addition funnel in 30-45 minutes. Reaction mass is cooled to 25-30°C and further stirred for 2 hour at 25-30°C. Solid appeared is filtered, washed with isopropyl alcohol (12 ml) and dried under vacuum at 40-45 °C to get the retigabine dihydrochloride form-II as off-white crystalline material.

CLAIMS:
We Claim:
1.A crystalline form I of retigabine dihydrochloride of formula I.

2. The crystalline form I of retigabine dihydrochloride according to claim 1 exhibit non-linear shape crystals a5 illustrated in figure II.
3. The crystalline form I of retigabine dihydrochloride according to claim 2 wherein non-linear shape is bi-pyramidal as shown in figure II.
4. The crystalline form I of retigabine dihydrochloride according to claim 1 exhibit an X ray powder diffraction pattern characterized by peaks at 29 values 5.89, 11.81, 12.78, 13.13, 13.74, 15.05, 15.40, 16.37, 16.91, 17.37, 17.78, 19.01, 19.62, 21.40, 22.03, 22.50, 23.41, 23.78, 24.23, 24.81, 25.26, 26.26, 26.64, 26.99, 27.73, 28.18, 28.49, 29.28, 29.85, 32.07, 32.42, 32.75, 33.61, 33.90, 34.38, 35.25, 36.00, 36.65, 37.38, 37.79, 38.47 (±0.2°, 20).
5. A process for the preparation of form I, comprising:
a) contacting retigabine base of formula II with an organic solvent;
b) contacting solution of step a) comprising retigabine base, in an organic solvent with HC1 to obtain solid crystalline retigabine dihydrochloride form I.


6. The organic solvent according to claim 5 a) is methanol.
7. A process for the preparation of form I, comprising:

a) contacting solid crystalline or amorphous retigabine dihydrochloride of formula I with water;
b) contacting solution of step a) comprising retigabine dihydrochloride in water with an organic solvent as an anti-solvent to obtain solid crystalline retigabine dihydrochloride form I.
8. The process according to claim 7 b) wherein organic solvent used as an anti-solvent is selected from the group comprising acetonitrile, acetone and mixture thereof.
9. A Process for the preparation of form II, comprising:
a) contacting retigabine base of formula II with an organic solvent;
b) contacting solution of step a) with HC1 to obtain solid crystalline retigabine dihydrochloride form II.
10. The process of claim 9 a) wherein organic solvent is further selected from
ethanol, isopropanol and mixture thereof.