WO2014179859A2 - Polymorphic form of ezogabine and process for the preparation thereof - Google Patents

Polymorphic form of ezogabine and process for the preparation thereof Download PDF

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Publication number
WO2014179859A2
WO2014179859A2 PCT/CA2014/000396 CA2014000396W WO2014179859A2 WO 2014179859 A2 WO2014179859 A2 WO 2014179859A2 CA 2014000396 W CA2014000396 W CA 2014000396W WO 2014179859 A2 WO2014179859 A2 WO 2014179859A2
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WIPO (PCT)
Prior art keywords
ezogabine
polymorphic form
organic solvent
form apo
range
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PCT/CA2014/000396
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French (fr)
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WO2014179859A3 (en
Inventor
Padiyath Mohammed AKBARALI
Ramana Kintali VENKATA
Trivedi NIKHIL
Hichanuru Rajashekaraiah MANJUNATHA
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Apotex Inc.
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Publication of WO2014179859A2 publication Critical patent/WO2014179859A2/en
Publication of WO2014179859A3 publication Critical patent/WO2014179859A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the present invention relates to a polymorphic form of Ezogabine. More particularly, the present invention relates to a polymorphic form of Ezogabine, processes for preparation thereof, and pharmaceutical formulations thereof.
  • Ezogabine also known as Retigabine, is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older.
  • Ezogabine is chemically known as N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester,
  • R1 ' R2' R3' R4' R5' Ar and Alk have the following meanings: where the symbols R ⁇ R 2 , R3, R4, R5, Ar and Alk have the following meanings: Ri : hydrogen, Ci -C 6 -alkyl, C 2 -C 6 -alkanoyl or the radical Ar; R 2 : hydrogen or C- ⁇ -C 6 -alkyl; R 3 : Ci -C 6 -alkoxy, NH 2 , Ci -C 6 -alkylamino, Ci -C 6 -dialkylamino, amino substituted by the radical Ar, Ci -CQ -alkyl, C2 -C 6 -alkenyl, C2 -CQ -alkynyl, the radical Ar or the radical ArO-; R4 : hydrogen, Ci -C6 -alkyl or the radical Ar; R 5 : hydrogen or Ci -C6 -alkyl or the radical Ar; Alk:
  • U.S. Patent No. 5, 914,425 discloses three crystalline forms of Ezogabine namely modification A, modification B and modification C and process for the preparation thereof.
  • U.S. Patent Application No. 2012/0053238 A1 discloses retigabine (ezogabine) in a non-crystalline form together with a surface stabilizer in the form of a stable intermediate and process for the preparation thereof.
  • CN Patent Application No. 102241608A relates to a retigabine compound in a semihydrate crystal form and a preparation method thereof.
  • the compound in the crystal form has the following good characteristics: the purity is high; and the stability is good, and the compound has superiority in industrial production and is suitable for preparation technological process and long-term storage.
  • the invention also relates to a pharmaceutical composition of the retigabine compound in the semihydrate crystal form and an application of the compound in preparation of antiepileptic medicaments.
  • PCT Publication No. 2013/008250 relates to crystalline modification D of retigabine, process for its preparation and processes for preparation of mixture of known retigabine modifications and pharmaceutical composition comprising thereof.
  • PCT Publication No. 2013/1 14379 relates to novel polymorphs of N-[2- amino-4-(4-fluorobenzylamino )-phenyl] carbamic acid ethyl ester, processes for preparing them, and pharmaceutical composition comprising them.
  • the invention relates to a novel crystalline polymorph of retigabine designated as crystalline Form I, characterized by XRPD having characteristic peaks at about 4.87, 5.04, 7.03, 9.74, 10.02, 1 1.6, 18.03, 19.9 and 28.5 +- 0.2 degrees two-theta, which is substantially same as depicted in Fig. 1 of WO 2013/1 14379.
  • the '379 publication also discloses Form II and process for the preparation thereof.
  • This invention is based, at least in part, on a polymorphic form of Ezogabine, termed herein as APO-I.
  • APO-I polymorphic form of Ezogabine of present invention
  • the polymorphic form APO-I of Ezogabine of present invention offers an improved solubility profile.
  • Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 5.6 ⁇ 0.2, 6.7 ⁇ 0.2, 7.8 ⁇ 0.2, 1 1.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.6 ⁇ 0.2 and 18.7 ⁇ 0.2.
  • Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein further comprising peaks, expressed in degrees 2-theta, at approximately 9.3 ⁇ 0.2, 14.0 ⁇ 0.2, 14.2 ⁇ 0.2, 20.2 ⁇ 0.2, 23.2 ⁇ 0.2, 24.55 ⁇ 0.2, 26.0 ⁇ 0.2, 31.9 ⁇ 0.2 and 34.7 ⁇ 0.2.
  • lllustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein characterized by a PXRD substantially similar to the PXRD depicted in Figure 1.
  • Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein characterized by a DSC thermogram comprising two endothermic peaks at about 130.8 ° C and about 141.6 ° C.
  • Illustrative embodiments of the invention provide a process for the preparation of a polymorphic form APO-I of Ezogabine comprising: (a) providing a solution of Ezogabine in an organic solvent and aqueous ammonia; (b) cooling the solution obtained in step (a) to about 50-65°C; (c) adding a non-polar organic solvent to the solution of step (b); and (d) isolating and / or recovering the polymorphic form APO-I of Ezogabine.
  • Illustrative embodiments of the invention provide a process described herein wherein the organic solvent used in dissolving is selected from the group consisting of: ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
  • Illustrative embodiments of the invention provide a process described herein wherein the organic solvent is ethyl acetate.
  • Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 1 % w/w to about 30% w/w.
  • Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 1 % to about 10% w/w.
  • Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 5% to about 10% w/w.
  • lllustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60° C to about 80° C.
  • Illustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60°C to about 70° C.
  • Illustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 65°C to about 70°C.
  • Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 50° to about 65° C.
  • Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 65°C.
  • Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 60°C.
  • Illustrative embodiments of the invention provide a process described herein wherein the non-polar organic solvent is selected from the group consisting of: Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers.
  • the non-polar organic solvent is selected from the group consisting of: Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers.
  • Illustrative embodiments of the invention provide a process described herein wherein the non-polar organic solvent is Heptane.
  • Illustrative embodiments of the invention provide a process described herein wherein isolating the polymorphic form APO-I of Ezogabine comprises at least one technique selected from the group consisting of: filtration, suction filtration, concentrating, decantation, centrifugation, and gravity filtration.
  • Illustrative embodiments of the invention provide a process described herein wherein the solution obtained from step (b) is seeded with crystals of the polymorphic form APO-I of Ezogabine before adding the non-polar organic solvent.
  • Illustrative embodiments of the invention provide a process described herein wherein the process further comprises drying the isolated polymorphic form APO-I of Ezogabine.
  • Illustrative embodiments of the invention provide a pharmaceutical composition comprising the polymorphic form APO-I of Ezogabine described herein and one or more pharmaceutically acceptable excipients.
  • Figure 1 is a Powder X-Ray Diffractogram (PXRD) of the polymorphic form
  • Figure 2 is a differential scanning calorimetry (DSC) thermogram of the polymorphic form APO-I of Ezogabine.
  • Figure 3 is an infrared (IR) absorption spectrum of the polymorphic form APO-I of Ezogabine .
  • the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
  • the term “approximately” means that the peak may vary by ⁇ 5 cm “1 of the subject value.
  • the term “approximately” means that the peak may vary by + 2 degrees centigrade of the subject value.
  • the term "peak” refers to a feature that one skilled in the art would recognize as not attributing to background noise.
  • an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 1 % when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
  • the present invention encompasses the polymorphic forms isolated in pure form or when admixed with other materials, for example other isomers and/or polymorphic forms and/or salt forms or any other material.
  • the present invention comprises a polymorphic form APO-I of Ezogabine.
  • An illustrative PXRD of the polymorphic form APO-I of Ezogabine obtained according to the present invention is shown in Figure 1.
  • the polymorphic form APO-I of Ezogabine may have a reflection ("peak") at any one or more of the values expressed in degrees 2-theta given in Table 1.
  • peak a reflection
  • values are given in the tables below, the form may be defined by the claimed peaks.
  • the polymorphic form APO-I of Ezogabine is characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 5.6 ⁇ 0.2, 6.7 ⁇ 0.2, 7.8 ⁇ 0.2, 1 1.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.6 ⁇ 0.2 and 18.7 ⁇ 0.2.
  • the polymorphic form APO-I is characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 9.3 ⁇ 0.2, 14.0 ⁇ 0.2, 14.2 ⁇ 0.2, 20.2 ⁇ 0.2, 23.2 ⁇ 0.2, 24.55 ⁇ 0.2, 26.0 ⁇ 0.2, 31.9 ⁇ 0.2 and 34.7 ⁇ 0.2.
  • the polymorphic form APO-I of Ezogabine is characterized by a PXRD substantially similar to the PXRD depicted in Figure 1.
  • the polymorphic form APO-I of Ezogabine is characterized by a DSC thermogram comprising two endothermic peaks at about 130.8° C and about 141.6° C.
  • the polymorphic form APO- I of Ezogabine is characterized by DSC thermogram comprising two endothermic peaks with peak onset temperatures of approximately 128.0° C and 140.7° C and peak maximum temperatures of approximately 130.8° C and 141.6° C, respectively.
  • the polymorphic form APO-I of Ezogabine is characterized by a DSC thermogram substantially similar to the DSC thermogram depicted in Figure 2.
  • the polymorphic form APO-I of Ezogabine is characterized by an IR spectrum substantially similar to the spectrum disclosed in Figure 3.
  • the polymorphic form APO-I of Ezogabine has a particle size d (0.9) of less than about 150 ⁇ and d (0.5) of less than about 50 ⁇ . In some embodiments, the polymorphic form APO-I of Ezogabine disclosed herein has particle size d (0.9) of less than or equal to about 100 ⁇ and d (0.5) of less than or equal to about 20 ⁇ .
  • the polymorphic form APO-I of Ezogabine may have improved solubility, reproducibility, chemical stability and polymorphic stability. In some embodiments, the polymorphic form APO-I of Ezogabine of present invention exhibits an improved solubility profile.
  • the present invention comprises a process for the preparation of a polymorphic form APO-I of Ezogabine comprising:
  • step (b) cooling the solution obtained in step (a) to about 50-65 ° C;
  • step (c) adding a non-polar organic solvent to the solution of step (b); and (d) isolating and / or recovering polymorphic form APO-I of
  • Step (a) of providing a solution of Ezogabine includes dissolving Ezogabine in a mixture of organic solvent and aqueous ammonia.
  • the organic solvent may be selected from, but not limited to, ethyl acetate, isopropyl acetate or butyl acetate and mixtures thereof, preferably ethyl acetate.
  • the concentration of aqueous ammonia used may vary in the range of 1 % to 30% w/w, preferably in the range of 1 % to 10% w/w, more preferably in the range of 5% to 10% w/w.
  • the solution of ezogabine can be prepared at any suitable temperatures preferably in the range of 60 - 80 C, more preferably in the range of 60 ° - 70 ° C, most preferably in the range of 65 - 70 ° C.
  • Step (b) of the process includes cooling the solution obtained in Step (a) to about 50-65 ° C.
  • the solution can be cooled to a temperature preferably in the range of 55-65 ° C, more preferably in the range of 55 -60 C.
  • the solution obtained in step (b) may optionally be seeded with the crystals of novel polymorphic form of Ezogabine of present invention before adding the non-polar organic solvent.
  • non-polar organic solvent is added to the reaction mixture of step (b).
  • the non-polar organic solvent may be selected from, but not limited to, Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers, preferably Heptane.
  • non-polar organic solvent is added to the reaction mixture of step (b) at a temperature in the range of 50 ° to 65 ° C, preferably in the range of 55 ° to 60 ° C.
  • the polymorphic form APO-I of Ezogabine is isolated by conventional techniques such as filtration, suction filtration, concentrating, decantation, centrifugation, gravity filtration, etc.
  • the isolated polymorphic form APO-I of Ezogabine is dried at a temperature in the range of 30 to 60 ° C, preferably in the range of 40 to 50 ° C under vacuum.
  • the drying can be carried out for any desired time period that provides the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. Drying equipment selection is well within the ordinary skill in the art.
  • the polymorphic form APO-I of Ezogabine obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of
  • polymorphic form APO-I of Ezogabine of the present invention disclosed herein may be used alone or in combination with one or more other active pharmaceutical ingredients in the preparation of pharmaceutical compositions together with one or more pharmaceutically acceptable excipients, carriers or diluents.
  • These pharmaceutical compositions 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.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that 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 by direct blending, dry granulation, and wet granulation or by extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.
  • Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
  • the polymorphic form APO-I of Ezogabine may be formulated into pharmaceutical formulations comprising pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients may include include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and others known to a person of skill in the art.
  • binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and others known to a person of skill in the art may be suitable excipients.
  • disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and others known to a person of skill in the art may be suitable excipients.
  • lubricants such as stearic acid, magnesium stearate, zinc stearate, and others known to a person of skill in the art may be suitable excipients.
  • glidants such as colloidal silicon dioxide and others known to a person of skill in the art may be suitable excipients.
  • solubility or wetting enhancers such as anionic, cationic, neutral surfactants and others known to a person of skill in the art may be suitable excipients.
  • complex forming agents such as various grades of cyclodextrins and resins and others known to a person of skill in the art may be suitable excipients.
  • release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and others known to a person of skill in the art may be suitable excipients.
  • film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and others known to a person of skill in the art may be suitable excipients.
  • the Powder X-ray Diffraction (PXRD) Analysis reported herein was acquired on a PAN analytical X-pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector.
  • the diffractometer was configured in Bragg- Brentano geometry; data was collected over a 2 ⁇ range of 5 to 35 using CuKa radiation at a power of 40mA and 45kV. CuK radiation was removed using a divergent beam Nickel filter. A step size of 0.017 degrees was used. A step time of
  • Samples were rotated at 1 Hz to reduce preferred orientation effects.
  • the samples were prepared by the back-loading technique.
  • the DSC thermogram reported herein was collected on a Mettler-Toledo 822e instrument. Samples (1 to 3mg) were weighed into a 40 ⁇ _ aluminium pan and were crimped closed with an aluminium lid. The samples were analysed under a flow of nitrogen (ca. 50mL/min) at a scan rate of 10 ° C per minute, from 30 ° to 250° C.
  • Particle Size Distribution was determined by laser diffraction in Malvern Master Sizer 2000 equipment.
  • Particle Size Distribution means the cumulative volume size distribution of equivalent spherical diameters.
  • the important characteristics of the PSD are the d (0.9), which is the size, in microns, below which 90% of the particles by volume are found, and the d (0.5), which is the size, in microns, below which 50% of the particles by volume are found.
  • a d (0.9) of less than 100 microns means that 90 volume-percent of the particles in a composition have a diameter less than 100 microns.
  • FT-IR spectroscopy was performed with a Perkin-Elmer IR spectrometer. For the production of KBr compacts approximately 3mg of sample was powdered with 300 mg of KBr. The spectra were recorded in transmission mode ranging from 4400 to 450 cm "1 .
  • Ezogabine used in the following examples may be prepared using the processes known in the prior art such as the process described in U.S. Patent No. 5,384,330.
  • Ezogabine (32.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (48 ml) and 10% w/w aqueous ammonia (1.6 ml) were added to the flask. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 60° to 65°C. Heptane (65 ml) was added slowly to the solution over a period of one hour and reaction mixture was continually stirred at 60° C. The reaction mass was slowly cooled to 30° to
  • Ezogabine (50.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (75 ml) and 10% w/w aqueous ammonia (5 ml) were added to the flask containing Ezogabine. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 55° to 60° C. The cooled solution was seeded with crystals of Ezogabine as prepared in
  • Example 1 and stirring was continued at 55° C to 60° C for 1 to 2 hrs.
  • Heptane 100 ml was added to the flask and stirring was continued for 1 hr at 55° C to 60° C.
  • the resulted mass was filtered, washed with heptane and dried at 50° C to obtain form APO-I of Ezogabine. Yield: 35.0 g.
  • Example 3
  • Ezogabine (15.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (22.5 ml) and 10% w/w aqueous ammonia (1.5 ml) were added to the flask containing Ezogabine. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 55° C to 60° C. The solution was seeded with crystals of Ezogabine as prepared in Example 1 (50 mg) and stirring was continued at 58° C for 1 to 2 hrs. Heptane (30 ml) was added to the solution and reaction mass was stirred for 2 hrs. The resulted material was filtered and dried to obtain form APO-I of Ezogabine.
  • Ezogabine APO-I polymorph samples were packed in an antistatic polyethylene bags and then placed in another polybag and heat sealed.
  • the double polybags were placed in aluminum foil, heat sealed and placed in an HDPE drum.
  • the samples were then tested for stability after storing at 25°+2° C and 60%+5% relative humidity (RH), for desired times, such as one, three, or six months.
  • RH relative humidity
  • Impurities, drug concentrations, polymorph stability and other parameters were measured at intervals during the storage. The results are set out in Table 2 below.
  • a comparative solubility profile of APO-I polymorph along with the crystalline modifications A, B and C is given in Table 3 below.
  • the solubility data of prior art polymorphs is reported in WO 2013/1 14379 and is used to compare with obtained solubility data of form APO-I of Ezogabine.

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Abstract

A polymorphic form APO-I of Ezogabine, processes for the preparation thereof and pharmaceutical formulations comprising the polymorphic form APO-I are provided.

Description

POLYMORPHIC FORM OF EZOGABINE AND PROCESS FOR THE
PREPARATION THEREOF
TECHNICAL FIELD
The present invention relates to a polymorphic form of Ezogabine. More particularly, the present invention relates to a polymorphic form of Ezogabine, processes for preparation thereof, and pharmaceutical formulations thereof.
BACKGROUND
Ezogabine, also known as Retigabine, is indicated as adjunctive treatment of partial-onset seizures in patients aged 18 years and older. Ezogabine is chemically known as N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester,
Figure imgf000002_0001
U.S. Patent No. 5,384,330 discloses pharmacologically active 1 ,2,4- triaminobenzene derivatives of the General Formula I:
Figure imgf000002_0002
where the symbols R1 ' R2' R3' R4' R5' Ar and Alk have the following meanings: where the symbols R^ R2, R3, R4, R5, Ar and Alk have the following meanings: Ri : hydrogen, Ci -C6 -alkyl, C2 -C6 -alkanoyl or the radical Ar; R2 : hydrogen or C-ι -C6 -alkyl; R3 : Ci -C6 -alkoxy, NH2, Ci -C6 -alkylamino, Ci -C6 -dialkylamino, amino substituted by the radical Ar, Ci -CQ -alkyl, C2 -C6 -alkenyl, C2 -CQ -alkynyl, the radical Ar or the radical ArO-; R4 : hydrogen, Ci -C6 -alkyl or the radical Ar; R5 : hydrogen or Ci -C6 -alkyl or the radical Ar; Alk: a straight or branched alkylene group containing 1-9 carbon atoms, which can also be substituted by the radical Ar.
U.S. Patent No. 5, 914,425 discloses three crystalline forms of Ezogabine namely modification A, modification B and modification C and process for the preparation thereof.
U.S. Patent Application No. 2012/0053238 A1 discloses retigabine (ezogabine) in a non-crystalline form together with a surface stabilizer in the form of a stable intermediate and process for the preparation thereof.
CN Patent Application No. 102241608A relates to a retigabine compound in a semihydrate crystal form and a preparation method thereof. The compound in the crystal form has the following good characteristics: the purity is high; and the stability is good, and the compound has superiority in industrial production and is suitable for preparation technological process and long-term storage. The invention also relates to a pharmaceutical composition of the retigabine compound in the semihydrate crystal form and an application of the compound in preparation of antiepileptic medicaments.
PCT Publication No. 2013/008250 relates to crystalline modification D of retigabine, process for its preparation and processes for preparation of mixture of known retigabine modifications and pharmaceutical composition comprising thereof.
PCT Publication No. 2013/1 14379 relates to novel polymorphs of N-[2- amino-4-(4-fluorobenzylamino )-phenyl] carbamic acid ethyl ester, processes for preparing them, and pharmaceutical composition comprising them. In one aspect, the invention relates to a novel crystalline polymorph of retigabine designated as crystalline Form I, characterized by XRPD having characteristic peaks at about 4.87, 5.04, 7.03, 9.74, 10.02, 1 1.6, 18.03, 19.9 and 28.5 +- 0.2 degrees two-theta, which is substantially same as depicted in Fig. 1 of WO 2013/1 14379. The '379 publication also discloses Form II and process for the preparation thereof.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a need in the art for novel polymorphic form of Ezogabine and a process of preparation thereof.
SUMMARY
This invention is based, at least in part, on a polymorphic form of Ezogabine, termed herein as APO-I. The polymorphic form APO-I of Ezogabine of present invention offers improved physical characteristics, which includes solubility, reproducibility, improved chemical stability and/or improved polymorphic stability. In particular, the polymorphic form APO-I of Ezogabine of present invention offers an improved solubility profile.
Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 5.6 ± 0.2, 6.7 ± 0.2, 7.8 ± 0.2, 1 1.4 ± 0.2, 13.4 ± 0.2, 16.6 ± 0.2 and 18.7 ± 0.2.
Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein further comprising peaks, expressed in degrees 2-theta, at approximately 9.3 ± 0.2, 14.0 ± 0.2, 14.2 ± 0.2, 20.2 ± 0.2, 23.2 ± 0.2, 24.55 ± 0.2, 26.0 ± 0.2, 31.9 ± 0.2 and 34.7 ± 0.2. lllustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein characterized by a PXRD substantially similar to the PXRD depicted in Figure 1.
Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein characterized by a DSC thermogram comprising two endothermic peaks at about 130.8° C and about 141.6° C.
Illustrative embodiments of the invention provide a polymorphic form APO- I of Ezogabine described herein characterized by a DSC thermogram
substantially similar to the DSC thermogram depicted in Figure 2.
Illustrative embodiments of the invention provide a process for the preparation of a polymorphic form APO-I of Ezogabine comprising: (a) providing a solution of Ezogabine in an organic solvent and aqueous ammonia; (b) cooling the solution obtained in step (a) to about 50-65°C; (c) adding a non-polar organic solvent to the solution of step (b); and (d) isolating and / or recovering the polymorphic form APO-I of Ezogabine.
Illustrative embodiments of the invention provide a process described herein wherein the organic solvent used in dissolving is selected from the group consisting of: ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
Illustrative embodiments of the invention provide a process described herein wherein the organic solvent is ethyl acetate.
Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 1 % w/w to about 30% w/w.
Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 1 % to about 10% w/w.
Illustrative embodiments of the invention provide a process described herein wherein the concentration of aqueous ammonia is in a range of from about 5% to about 10% w/w. lllustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60° C to about 80° C.
Illustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60°C to about 70° C.
Illustrative embodiments of the invention provide a process described herein wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 65°C to about 70°C.
Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 50° to about 65° C.
Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 65°C.
Illustrative embodiments of the invention provide a process described herein wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 60°C.
Illustrative embodiments of the invention provide a process described herein wherein the non-polar organic solvent is selected from the group consisting of: Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers.
Illustrative embodiments of the invention provide a process described herein wherein the non-polar organic solvent is Heptane.
Illustrative embodiments of the invention provide a process described herein wherein isolating the polymorphic form APO-I of Ezogabine comprises at least one technique selected from the group consisting of: filtration, suction filtration, concentrating, decantation, centrifugation, and gravity filtration.
Illustrative embodiments of the invention provide a process described herein wherein the solution obtained from step (b) is seeded with crystals of the polymorphic form APO-I of Ezogabine before adding the non-polar organic solvent.
Illustrative embodiments of the invention provide a process described herein wherein the process further comprises drying the isolated polymorphic form APO-I of Ezogabine.
Illustrative embodiments of the invention provide a pharmaceutical composition comprising the polymorphic form APO-I of Ezogabine described herein and one or more pharmaceutically acceptable excipients.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS
In drawings which illustrate embodiments of the invention,
Figure 1 is a Powder X-Ray Diffractogram (PXRD) of the polymorphic form
APO-I of Ezogabine.
Figure 2 is a differential scanning calorimetry (DSC) thermogram of the polymorphic form APO-I of Ezogabine.
Figure 3 is an infrared (IR) absorption spectrum of the polymorphic form APO-I of Ezogabine .
DETAILED DESCRIPTION
When used in reference to a diffractogram, a spectrum and/or data presented in a graph, the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
When used in reference to a peak in a powder X-ray diffractogram
(PXRD), the term "approximately" means that the peak may vary by ±0.2 degrees 2-theta of the subject value.
As used herein, when used in reference to a peak in an Infrared (IR) absorption spectrum, the term "approximately" means that the peak may vary by ±5 cm"1 of the subject value.
As used herein, when used in reference to a peak in a differential scanning calorimetry (DSC) thermogram, the term "approximately" means that the peak may vary by + 2 degrees centigrade of the subject value.
As used herein, when referring to a diffractogram, spectrum and/or to data presented in a graph, the term "peak" refers to a feature that one skilled in the art would recognize as not attributing to background noise.
Depending on the nature of the methodology applied and the scale selected to display results obtained from an X-ray diffraction analysis, an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 1 % when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
The present invention encompasses the polymorphic forms isolated in pure form or when admixed with other materials, for example other isomers and/or polymorphic forms and/or salt forms or any other material.
In some embodiments, the present invention comprises a polymorphic form APO-I of Ezogabine. An illustrative PXRD of the polymorphic form APO-I of Ezogabine obtained according to the present invention is shown in Figure 1. According to Figure 1 , the polymorphic form APO-I of Ezogabine may have a reflection ("peak") at any one or more of the values expressed in degrees 2-theta given in Table 1. Although values are given in the tables below, the form may be defined by the claimed peaks.
Table 1 : The Polymorphic Form APO-I of Ezogabine
Peak (degrees 2-theta) d-spacing (A°) Rel. Intensity (l/l0 %)
4.6795 18.8839 0.17
5.6180 15.731 1 14.77
6.701 1 13.1908 2.40
7.8470 1 1.2669 10.36
9.3576 9.4512 1.67
10.1375 8.7258 0.31
1 1.4009 7.7615 7.50
13.3941 6.6107 1 1.79
14.0287 6.3130 1.30
14.2644 6.2092 1.46
15.5539 5.6972 0.75
15.91 13 5.5700 0.51
16.5927 5.3428 6.26
18.7443 4.7341 100.00
20.2859 4.3777 10.87
21.9854 4.0430 0.34
22.4395 3.9622 1.18
22.9413 3.8766 3.35
23.2825 3.8206 7.1 1
24.4038 3.6475 1 1.51 Table 1 : The Polymorphic Form APO-I of Ezogabine
Peak (degrees 2-theta) d-spacing (A°) Rel. Intensity (l/l0 %)
24.5495 3.6262 7.22
25.4206 3.5039 0.26
26.0922 3.4152 2.91
26.6517 3.3447 0.63
27.2261 3.2755 0.90
27.8829 3.1998 1.28
28.6922 3.1 1 14 0.73
29.3278 3.0453 1.44
39.4261 2.9379 0.31
31.9651 2.7999 1 .37
32.371 1 2.7657 0.34
33.1 131 2.7054 0.65
33.4192 2.6813 0.67
34.7440 2.5820 2.07
35.1327 2.5543 0.10
36.2325 2.4793 0.44
37.8448 2.3773 0.76
39.3831 2.2879 0.31
In some embodiments, the polymorphic form APO-I of Ezogabine is characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 5.6 ± 0.2, 6.7 ± 0.2, 7.8 ± 0.2, 1 1.4 ± 0.2, 13.4 ± 0.2, 16.6 ± 0.2 and 18.7 ± 0.2. In some embodiments, the polymorphic form APO-I is characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 9.3 ± 0.2, 14.0 ± 0.2, 14.2 ± 0.2, 20.2 ± 0.2, 23.2 ± 0.2, 24.55 ± 0.2, 26.0 ± 0.2, 31.9 ± 0.2 and 34.7 ± 0.2. In some embodiments the polymorphic form APO-I of Ezogabine is characterized by a PXRD substantially similar to the PXRD depicted in Figure 1. ln some embodiments, the polymorphic form APO-I of Ezogabine is characterized by a DSC thermogram comprising two endothermic peaks at about 130.8° C and about 141.6° C. In other embodiments, the polymorphic form APO- I of Ezogabine is characterized by DSC thermogram comprising two endothermic peaks with peak onset temperatures of approximately 128.0° C and 140.7° C and peak maximum temperatures of approximately 130.8° C and 141.6° C, respectively. In other embodiments, the polymorphic form APO-I of Ezogabine is characterized by a DSC thermogram substantially similar to the DSC thermogram depicted in Figure 2.
In some embodiments, the polymorphic form APO-I of Ezogabine is characterized by an IR spectrum substantially similar to the spectrum disclosed in Figure 3.
In some embodiments, the polymorphic form APO-I of Ezogabine has a particle size d (0.9) of less than about 150 μητι and d (0.5) of less than about 50 μιτι. In some embodiments, the polymorphic form APO-I of Ezogabine disclosed herein has particle size d (0.9) of less than or equal to about 100 μιτι and d (0.5) of less than or equal to about 20 μηι.
In some embodiments, the polymorphic form APO-I of Ezogabine may have improved solubility, reproducibility, chemical stability and polymorphic stability. In some embodiments, the polymorphic form APO-I of Ezogabine of present invention exhibits an improved solubility profile.
In some embodiments, the present invention comprises a process for the preparation of a polymorphic form APO-I of Ezogabine comprising:
(a) providing a solution of Ezogabine in an organic solvent and aqueous ammonia;
(b) cooling the solution obtained in step (a) to about 50-65° C;
(c) adding a non-polar organic solvent to the solution of step (b); and (d) isolating and / or recovering polymorphic form APO-I of
Ezogabine.
Step (a) of providing a solution of Ezogabine includes dissolving Ezogabine in a mixture of organic solvent and aqueous ammonia. The organic solvent may be selected from, but not limited to, ethyl acetate, isopropyl acetate or butyl acetate and mixtures thereof, preferably ethyl acetate.
In the embodiment of step (a), the concentration of aqueous ammonia used may vary in the range of 1 % to 30% w/w, preferably in the range of 1 % to 10% w/w, more preferably in the range of 5% to 10% w/w.
In the embodiments of step (a), the solution of ezogabine can be prepared at any suitable temperatures preferably in the range of 60 - 80 C, more preferably in the range of 60° - 70° C, most preferably in the range of 65 - 70° C.
Step (b) of the process includes cooling the solution obtained in Step (a) to about 50-65° C. The solution can be cooled to a temperature preferably in the range of 55-65° C, more preferably in the range of 55 -60 C.
In a further embodiment, the solution obtained in step (b) may optionally be seeded with the crystals of novel polymorphic form of Ezogabine of present invention before adding the non-polar organic solvent.
In the embodiments of step (c), non-polar organic solvent is added to the reaction mixture of step (b). The non-polar organic solvent may be selected from, but not limited to, Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers, preferably Heptane.
In the embodiments of step (c), non-polar organic solvent is added to the reaction mixture of step (b) at a temperature in the range of 50° to 65° C, preferably in the range of 55° to 60° C.
In the embodiments of step (d), the polymorphic form APO-I of Ezogabine is isolated by conventional techniques such as filtration, suction filtration, concentrating, decantation, centrifugation, gravity filtration, etc.
In the embodiments of step (d), the isolated polymorphic form APO-I of Ezogabine is dried at a temperature in the range of 30 to 60° C, preferably in the range of 40 to 50° C under vacuum. The drying can be carried out for any desired time period that provides the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. Drying equipment selection is well within the ordinary skill in the art.
The polymorphic form APO-I of Ezogabine obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
Further, the polymorphic form APO-I of Ezogabine of the present invention disclosed herein may be used alone or in combination with one or more other active pharmaceutical ingredients in the preparation of pharmaceutical compositions together with one or more pharmaceutically acceptable excipients, carriers or diluents. These pharmaceutical compositions 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 that 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 by direct blending, dry granulation, and wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
The polymorphic form APO-I of Ezogabine may be formulated into pharmaceutical formulations comprising pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may include include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and others known to a person of skill in the art. Further, binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and others known to a person of skill in the art may be suitable excipients. Further still, disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and others known to a person of skill in the art may be suitable excipients. Further still, lubricants such as stearic acid, magnesium stearate, zinc stearate, and others known to a person of skill in the art may be suitable excipients. Further still, glidants such as colloidal silicon dioxide and others known to a person of skill in the art may be suitable excipients. Further still, solubility or wetting enhancers such as anionic, cationic, neutral surfactants and others known to a person of skill in the art may be suitable excipients. Further still, complex forming agents such as various grades of cyclodextrins and resins and others known to a person of skill in the art may be suitable excipients. Further still, release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and others known to a person of skill in the art may be suitable excipients. Further still, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and others known to a person of skill in the art may be suitable excipients.
EXAMPLES
The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in any way.
The Powder X-ray Diffraction (PXRD) Analysis reported herein was acquired on a PAN analytical X-pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector. The diffractometer was configured in Bragg- Brentano geometry; data was collected over a 2Θ range of 5 to 35 using CuKa radiation at a power of 40mA and 45kV. CuK radiation was removed using a divergent beam Nickel filter. A step size of 0.017 degrees was used. A step time of
20 seconds was used. Samples were rotated at 1 Hz to reduce preferred orientation effects. The samples were prepared by the back-loading technique.
The DSC thermogram reported herein was collected on a Mettler-Toledo 822e instrument. Samples (1 to 3mg) were weighed into a 40μΙ_ aluminium pan and were crimped closed with an aluminium lid. The samples were analysed under a flow of nitrogen (ca. 50mL/min) at a scan rate of 10° C per minute, from 30° to 250° C.
Particle Size Distribution (PSD) was determined by laser diffraction in Malvern Master Sizer 2000 equipment. Particle Size Distribution means the cumulative volume size distribution of equivalent spherical diameters. The important characteristics of the PSD are the d (0.9), which is the size, in microns, below which 90% of the particles by volume are found, and the d (0.5), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a d (0.9) of less than 100 microns means that 90 volume-percent of the particles in a composition have a diameter less than 100 microns. FT-IR spectroscopy was performed with a Perkin-Elmer IR spectrometer. For the production of KBr compacts approximately 3mg of sample was powdered with 300 mg of KBr. The spectra were recorded in transmission mode ranging from 4400 to 450 cm"1.
Ezogabine used in the following examples may be prepared using the processes known in the prior art such as the process described in U.S. Patent No. 5,384,330.
Example 1
Ezogabine (32.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (48 ml) and 10% w/w aqueous ammonia (1.6 ml) were added to the flask. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 60° to 65°C. Heptane (65 ml) was added slowly to the solution over a period of one hour and reaction mixture was continually stirred at 60° C. The reaction mass was slowly cooled to 30° to
35° C over a period of 1 to 2 hrs. The material was filtered and washed with heptane. The resulted solid was dried at 50° C to obtain form APO-I of Ezogabine. Yield: 28.0 g Example 2
Ezogabine (50.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (75 ml) and 10% w/w aqueous ammonia (5 ml) were added to the flask containing Ezogabine. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 55° to 60° C. The cooled solution was seeded with crystals of Ezogabine as prepared in
Example 1 and stirring was continued at 55° C to 60° C for 1 to 2 hrs. Heptane (100 ml) was added to the flask and stirring was continued for 1 hr at 55° C to 60° C. The resulted mass was filtered, washed with heptane and dried at 50° C to obtain form APO-I of Ezogabine. Yield: 35.0 g. Example 3
Ezogabine (15.0 g) was taken in a round bottomed flask fitted with condenser and temperature inlet. Ethyl acetate (22.5 ml) and 10% w/w aqueous ammonia (1.5 ml) were added to the flask containing Ezogabine. The mixture was heated to 70° C to get a clear solution. The solution was cooled to 55° C to 60° C. The solution was seeded with crystals of Ezogabine as prepared in Example 1 (50 mg) and stirring was continued at 58° C for 1 to 2 hrs. Heptane (30 ml) was added to the solution and reaction mass was stirred for 2 hrs. The resulted material was filtered and dried to obtain form APO-I of Ezogabine.
Yield: 14.9 g.
Example 4
Ezogabine APO-I polymorph samples were packed in an antistatic polyethylene bags and then placed in another polybag and heat sealed. The double polybags were placed in aluminum foil, heat sealed and placed in an HDPE drum. The samples were then tested for stability after storing at 25°+2° C and 60%+5% relative humidity (RH), for desired times, such as one, three, or six months. Impurities, drug concentrations, polymorph stability and other parameters were measured at intervals during the storage. The results are set out in Table 2 below.
Table 2 - Impurity Profile of Ezogabine APO-I Polymorph During Storage
Single
Max.
Condition Description Un M^wn Purity DSC XRPD
Jnknowi
Impurity
Initial Off white Q.04% 99.89% Complies Complies
25 ± 2°C nff° h t
& 1 month UTT ™e 0.03% 99.87% Complies Complies0 ± 5% RH off h-t
2 month un w™e 0.05% 99.87% Complies Complies Table 2 - Impurity Profile of Ezogabine APO-I Polymorph During Storage
Single
Condition Ji Max.
escription Purity DSC XRPD Peme D
riod Unknown
Impurity
Off white
3 month 0.04% 99.89% Complies Complies solid
Off white
6 month 0.07% 99.80% Complies Complies solid
Example 5
A comparative solubility profile of APO-I polymorph along with the crystalline modifications A, B and C is given in Table 3 below. The solubility data of prior art polymorphs is reported in WO 2013/1 14379 and is used to compare with obtained solubility data of form APO-I of Ezogabine.
Figure imgf000018_0001
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Furthermore, material appearing in the background section of the specification is not an admission that such material is prior art to the invention. Any priority document(s) are incorporated herein by reference as if each individual priority document were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

What is claimed is:
1. A polymorphic form APO-I of Ezogabine characterized by a PXRD comprising peaks, expressed in degrees 2-theta, at approximately 5.6 ± 0.2, 6.7 ± 0.2, 7.8 ± 0.2, 1 1.4 ± 0.2, 13.4 ± 0.2, 16.6 ± 0.2 and 18.7 ± 0.2.
2. The polymorphic form APO-I of Ezogabine of claim 1 further comprising peaks, expressed in degrees 2-theta, at approximately 9.3 ± 0.2, 14.0 ± 0.2, 14.2 ± 0.2, 20.2 ± 0.2, 23.2 ± 0.2, 24.55 ± 0.2, 26.0 ± 0.2, 31.9 ± 0.2 and 34.7 ± 0.2.
3. The polymorphic form APO-I of Ezogabine of claim 1 characterized by a PXRD substantially similar to the PXRD depicted in Figure 1.
4. The polymorphic form APO-I of Ezogabine of any one of claims 1 to 3 characterized by a DSC thermogram comprising two endothermic peaks at about
130.8° C and about 141.6° C.
5. The polymorphic form APO-I of Ezogabine of claim 4 characterized by a DSC thermogram substantially similar to the DSC thermogram depicted in Figure 2.
6. A process for the preparation of a polymorphic form APO-I of Ezogabine comprising:
(a) providing a solution of Ezogabine in an organic solvent and aqueous ammonia;
(b) cooling the solution obtained in step (a) to about 50-65° C;
(c) adding a non-polar organic solvent to the solution of step (b); and
(d) isolating and / or recovering the polymorphic form APO-I of Ezogabine.
7. The process of claim 6 wherein the organic solvent of step (a) is selected from the group consisting of: ethyl acetate, isopropyl acetate, butyl acetate and mixtures thereof.
8. The process of claim 7 wherein the organic solvent is ethyl acetate.
9. The process of any one of claims 6 to 8 wherein the concentration of aqueous ammonia is in a range of from about 1 % w/w to about 30% w/w.
10. The process of claim 9 wherein the concentration of aqueous ammonia is in a range of from about 1 % to about 10% w/w.
1 1. The process of claim 9 wherein the concentration of aqueous ammonia is in a range of from about 5% to about 10% w/w.
12. The process of any one of claims 6 to 11 wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60° C to about 80° C.
13. The process of any one of claims 6 to 1 1 wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 60°C to about 70° C.
14. The process of any one of claims 6 to 1 1 wherein dissolving Ezogabine in an organic solvent and aqueous ammonia is carried out at a temperature in the range of from about 65°C to about 70°C.
15. The process of any one of claims 6 to 14 wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 50° to about 65° C.
16. The process of any one of claims 6 to 14 wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 65°C.
17. The process of any one of claims 6 to 14 wherein non-polar organic solvent is added to the solution obtained from step (b) at a temperature in the range of from about 55°C to about 60°C.
18. The process of any one of claims 6 to 17 wherein the non-polar organic solvent is selected from the group consisting of: Pentane, Hexane, Heptane, Cyclopentane, Cyclohexane, Toluene and ethers.
19. The process of claim 18 wherein the non-polar organic solvent is Heptane.
20. The process of any one of claims 6 to 19 wherein isolating the polymorphic form APO-I of Ezogabine comprises at least one technique selected from the group consisting of: filtration, suction filtration, concentrating, decantation, centrifugation, and gravity filtration.
21 . The process of any one of claims 6 to 20 wherein the solution obtained from step (b) is seeded with crystals of the polymorphic form APO-I of Ezogabine before adding the non-polar organic solvent.
22. The process of any one of claims 6 to 21 wherein the process further comprises drying the isolated polymorphic form APO-I of Ezogabine.
23. A pharmaceutical composition comprising the polymorphic form APO-I of Ezogabine of any one of claims 1 to 5 and one or more pharmaceutically acceptable excipients.
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