WO2014023270A1 - Salts or co-crystals of ethyl n-[2-amino-4-[(4-fluorophenyl)methylamino]-phenyl]carbamate - Google Patents
Salts or co-crystals of ethyl n-[2-amino-4-[(4-fluorophenyl)methylamino]-phenyl]carbamate Download PDFInfo
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- WO2014023270A1 WO2014023270A1 PCT/CZ2012/000077 CZ2012000077W WO2014023270A1 WO 2014023270 A1 WO2014023270 A1 WO 2014023270A1 CZ 2012000077 W CZ2012000077 W CZ 2012000077W WO 2014023270 A1 WO2014023270 A1 WO 2014023270A1
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- Prior art keywords
- salt
- crystal
- ethyl
- methylamino
- fluorophenyl
- Prior art date
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- 239000013078 crystal Substances 0.000 title claims abstract description 117
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 150000003839 salts Chemical class 0.000 title claims abstract description 104
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 30
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 30
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 15
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000001530 fumaric acid Substances 0.000 claims abstract description 15
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 7
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000008107 benzenesulfonic acids Chemical class 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000002238 fumaric acids Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000003870 salicylic acids Chemical class 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims 12
- 125000005233 alkylalcohol group Chemical group 0.000 claims 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 24
- 238000004458 analytical method Methods 0.000 description 20
- 238000002411 thermogravimetry Methods 0.000 description 18
- 229960003312 retigabine Drugs 0.000 description 17
- 239000012535 impurity Substances 0.000 description 14
- 238000012986 modification Methods 0.000 description 10
- 230000004048 modification Effects 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 6
- 238000010309 melting process Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001757 thermogravimetry curve Methods 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000013019 agitation Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001955 cumulated effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- WSGFOWNASITQHJ-UHFFFAOYSA-N ethyl n-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate;dihydrochloride Chemical compound Cl.Cl.C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 WSGFOWNASITQHJ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 0 CCC(C)*(C)CC(*)CNCC*(C)(C)C1C(C)CC(C)C(C)(C)C1 Chemical compound CCC(C)*(C)CC(*)CNCC*(C)(C)C1C(C)CC(C)C(C)(C)C1 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- -1 Ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate compound Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to new salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino] phenyl]carbamate of formula I,
- retigabine in a solid form suitable for oral administration, method of their production and their use i pharmaceutical composition.
- Ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate compound which is also known as retigabine (CAS no. 150812-12-7) has anticonvulsive, antipyretic and analgesic activity which are effectively used in pharmaceutical preparation.
- the non-proprietary name retigabine is superseded by ezogabine in the United States of America.
- the preparation of retigabine dihydrochloride and similar compounds are described in patent US5384330.
- Solid retigabine in non-crystalline form is described in patent application WO2010105823 using surface stabilization. Methods for producing retigabine in solid, non-crystalline form and pharmaceutical formulations containing solid, noncrystalline retigabine are also given.
- a stable and amorphous solid mixture of retigabine is disclosed in patent application WO201 1039369.
- the pharmaceutically acceptable carriers and processes for preparing the amorphous forms of the compound are also detailed.
- the invention provides new salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino] phenyl]carbamate of formula I, known under the nonproprietary name retigabine, in a solid form suitable for oral administration and a method of their production.
- the salts or co-crystals are prepared from retigabine in the base form by reaction with an inorganic or organic acid in a suitable solvent or in mixtures of solvents.
- prepared new salts or co-crystals are suitable for use in pharmaceutical dosage forms.
- An advantage of the newly prepared salts or co-crystals consists in their stability during storage and in suitable physical and chemical characteristics for formulation of a dosage form.
- the present invention further relates to pharmaceutical formulations containing the novel salts or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and the use thereof for the treatment of neuropathic pain and epilepsy.
- ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate salts or co- crystals of the present invention are as follows:
- the present invention relates to a salt or co-crystal of
- one acid selected from the group consisting of hydrobromic acid, hydrochloric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid and salicylic acid.
- inventive salts or co-crystals of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate can be obtained with acceptable yields and high purity.
- inventive salts or co-crystals formed from ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and at least one pharmaceutically acceptable component are preferably presented in crystalline or amorphous form, more preferably the inventive salt or co-crystal formed from ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and at least one pharmaceutically acceptable component is crystalline.
- the inventively claimed salt or co-crystal may be an anhydrous and/or solvent-free form or be a hyd rated/sol vated form.
- inventive salt or co-crystals may exist in different solid forms with different internal structures (polymorphism), which may have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt or co-crystal. Therefore, crystalline modifications of the inventive salt or co-crystal cover individual crystals and/or mixtures thereof in any ratio.
- the production of a retigabine salt or co-crystal according to the invention is carried out by conversion of the compound of formula I
- the conversion is preferably carried out using a solvent selected from ketones, ethers, esters, amides or nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons and water or their mixtures. More preferably, the solvent is selected from C1-C4 alkyl alcohols, esters or their mixtures. Most preferably, the solvent is methanol, ethanol, ethyl acetate or their mixtures.
- the conversion is preferably carried out using 0.95 to -1 .05 molar equivalents of the acid.
- the resulting salt is crystallized at a temperature of from -30 °C to the boiling point of the solvent.
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and hydrobromic acid according to the invention has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (XPERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid has the following most characteristic powder diffraction peaks illustrated in Table , below:
- the salt or co-crystal is characterized by the following peaks: 1 1.74; 19.22; 20.50; 24.46° 2 ⁇ ⁇ 0.2° 2 ⁇ ., more preferably, 1 1 .74; 17.68; 19.22; 20.50; 21.62; 24.46; 29.51 ; 33.04° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrobromic acid can be further characterized by thermal analytical methods.
- Figure 2 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 3 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrobromide salt or co-crystal shows a 0.7% weigth loss in the range of 20°C-to 00°C.
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and hydrochloric acid according to the invention has the characteristic XRPD pattern as shown in Figure 4. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
- the salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid has the following most characteristic powder diffraction peaks illustrated in Table 2, below: Pos. d-spacing Rel. Int.
- the salt or co-crystal is characterized by the following peaks: 12.01 ; 17.98; 23.99° 2 ⁇ ⁇ 0.2° 2 ⁇ , more preferably, 12.01 ; 17.98; 19.74; 23.99; 26.61 ; 30.07° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrochloric acid can be further characterized by thermal analytical methods.
- Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 6 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrochloride salt or co-crystal shows a 0.3% weigth loss in the range of 20°C-to 100°C.
- the DSC measurement gives a melting process with
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 7.
- XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
- the salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and methanesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 3, below:
- the salt or co-crystal is characterized by the following peaks: 5.37; 1 1.38; 17.10° 2 ⁇ ⁇ 0.2° 2 ⁇ , more preferably, 5.37; 1 1.38; 14.07; 17.10; 19.27; 21 .99; 23.90° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and methanesulphonic acid can be further characterized by thermal analytical methods.
- Figure 8 shows the DSC (Perkin Elmer Pyris 1 DSC) and
- Figure 9 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrochloride salt or co-crystal shows a 2.5% weigth loss in the range of 20°C-to 100°C.
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and benzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 10. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
- the salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and benzenesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 4, below:
- the salt or co-crystal is characterized by the following peaks: 5.14; 19.75° 2 ⁇ ⁇ 0.2° 2 ⁇ , more preferably, 5.14; 8.13; 9.33; 14.40; 19.75; 22.85° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and benzenesulphonic acid can be further characterized by thermal analytical methods.
- Figure 11 shows the DSC (Perkin Elmer Pyris 1 DSC) and
- Figure 12 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrochloride salt or co-crystal shows a 0.4% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and fumaric acid according to the invention has the characteristic XRPD pattern as shown in Figure 13. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
- the salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and fumaric acid has the following most characteristic powder diffraction peaks illustrated in Table 5, below: Pos. d-spacing Rel. Int.
- the salt or co-crystal is characterized by the following peaks: 6.79; 12.34; 22.60° 2 ⁇ ⁇ 0.2° 2 ⁇ , more preferably, 6.79; 12.34; 15.67; 17.65; 19.64; 20.49; 22.60; 25.18° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and fumaric acid can be further characterized by thermal analytical methods.
- Figure 14 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 15 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrochloride salt or co-crystal shows a 0.2% weigth loss in the range of 20°C-to 100°C.
- the DSC measurement gives a melting process with Tonseu
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and salicylic acid according to the invention has the characteristic XRPD pattern as shown in Figure 16. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X ' PERT PRO MPD PANalytical).
- the salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and salicylic acid has the following most characteristic powder diffraction peaks illustrated in Table 6, below:
- the salt or co-crystal is characterized by the following peaks: 6.93; 17.93; 19.83° 2 ⁇ ⁇ 0.2° 2 ⁇ , more preferably, 6.93; 17.93; 19.83; 22.14; 25.72; 28.42° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and salicylic acid can be further characterized by thermal analytical methods.
- FIG. 17 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 18 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively.
- Hydrochloride salt or co-crystal shows a 0.2% weigth loss in the range of 20°C-to 100°C.
- novel salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate of the present invention possess better solubility properties compared to the solubility of the modification A of ethyl N-[2- amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate which can be found in the original drug product.
- Figure 1 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
- Figure 2 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
- Figure 3 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
- Figure 4 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid.
- Figure 5 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid.
- Figure 6 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid.
- Figure 7 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
- Figure 8 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
- Figure 9 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
- Figure 10 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid.
- Figure 11 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid.
- Figure 12 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid.
- Figure 13 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
- Figure 14 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
- Figure 15 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
- Figure 16 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid.
- Figure 17 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid.
- Figure 18 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid.
- Sample were measured as received on Si plate (zero background holder).
- Incident beam optics programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/4° anti-scatter fixed slit, 0.02 rad soller slits.
- Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122°, 0.02 rad soller slits, anti-scatter slit 5.0 mm, Ni filter.
- DSC measurements were performed on a Perkin Elmer Pyris 1 DSC.
- the sample were weighed in aluminium pans and covers (20 ⁇ _) and measured in a nitrogen flow. Investigations were performed in a temperature range of 50°C to 250°C with a heating rate of 10°C/min.
- the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks.
- the specific heat is given in J/g.
- the weight sample was about 3 mg.
- TGA were performed on a Perkin Elmer " RGA 6.
- the samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 25°C to 300°C with a heating rate of 10°C/min.
- the weight sample was about 13-18 mg.
- the samples were weighted in Petri dishes and placed into the oven for 24 hours.
- the investigations were performed at 80°C and ambient humidity, under atmospheric pressure.
- the samples were weighted in Eppendorf tubes and diluted with 1 mL of water.
- the investigations were performed at 37°C using an agitation of 900 rpm for 24 hours.
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Abstract
A salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and one acid selected from the group consisting of hydrobromic acid, hydrochloric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid and salicylic acid.
Description
Salts or co-crystals of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate
Technical Field
The invention relates to new salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino] phenyl]carbamate of formula I,
I
known under the name retigabine, in a solid form suitable for oral administration, method of their production and their use i pharmaceutical composition.
Background Art Ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate compound which is also known as retigabine (CAS no. 150812-12-7) has anticonvulsive, antipyretic and analgesic activity which are effectively used in pharmaceutical preparation. The non-proprietary name retigabine is superseded by ezogabine in the United States of America. The preparation of retigabine dihydrochloride and similar compounds are described in patent US5384330.
CNS Drug Reviews. 2005, 1 1 , 1 describes retigabine dihydrochloride as an easily prepared but hygroscopic and unstable compound under medium to long-term storage at -18°C. It is recommended to store as free base isolated from light, preferably. A tendency of retigabine to easily oxidize upon contact with air during solubilization is also described.
Three different crystalline modifications of retigabine are disclosed in patent US5914425, denominated therein as modifications A, B and CA and processes for preparing them are also provided.
Solid retigabine in non-crystalline form is described in patent application WO2010105823 using surface stabilization. Methods for producing retigabine in solid, non-crystalline form and pharmaceutical formulations containing solid, noncrystalline retigabine are also given.
A stable and amorphous solid mixture of retigabine is disclosed in patent application WO201 1039369. The pharmaceutically acceptable carriers and processes for preparing the amorphous forms of the compound are also detailed.
An improved process for preparing retigabine with improved colour quality is described in patent application WO201 1 101456.
Based on stability and photostability data it is proposed to store retigabine protected from light as darkening of the active substance may occur if exposed to light. While modification A of retigabine was found to be stable under long-term storage at temperature up to 60°C and at relative humidity up to 70%, there is still a great interest of preparing the compound of Formula I in stable form.
Disclosure of Invention
The invention provides new salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino] phenyl]carbamate of formula I, known under the nonproprietary name retigabine, in a solid form suitable for oral administration and a method of their production.
The salts or co-crystals are prepared from retigabine in the base form by reaction with an inorganic or organic acid in a suitable solvent or in mixtures of solvents. Thus prepared new salts or co-crystals are suitable for use in pharmaceutical dosage forms. An advantage of the newly prepared salts or co-crystals consists in their stability during storage and in suitable physical and chemical characteristics for formulation of a dosage form.
The present invention further relates to pharmaceutical formulations containing the novel salts or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and the use thereof for the treatment of neuropathic pain and epilepsy.
The ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate salts or co- crystals of the present invention are as follows:
A) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny ]carbamate and hydrobromic acid;
B) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny ]carbamate and hydrochloric acid;
C) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny ]carbamate and methanesulphonic acid;
D) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny ]carbamate and benzenesulphonic acid;
E) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny ]carbamate and fumaric acid;
F) the sa t or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- pheny Jcarbamate and salicylic acid.
Detailed Description of the Invention
The present invention relates to a salt or co-crystal of
ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate
and
one acid selected from the group consisting of hydrobromic acid, hydrochloric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid and salicylic acid.
The inventive salts or co-crystals of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate can be obtained with acceptable yields and high purity.
The inventive salts or co-crystals formed from ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and at least one pharmaceutically acceptable component are preferably presented in crystalline or amorphous form, more preferably the inventive salt or co-crystal formed from ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and at least one pharmaceutically acceptable component is crystalline.
The inventively claimed salt or co-crystal may be an anhydrous and/or solvent-free form or be a hyd rated/sol vated form.
The inventive salt or co-crystals may exist in different solid forms with different internal structures (polymorphism), which may have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt or co-crystal. Therefore, crystalline modifications of the inventive salt or co-crystal cover individual crystals and/or mixtures thereof in any ratio. The production of a retigabine salt or co-crystal according to the invention is carried out by conversion of the compound of formula I
(I) to a salt by reaction with an acid selected from the group consisting of hydrobromic, hydrochloric, methanesulphonic, benzenesulphonic, fumaric and salicylic acids. The conversion is preferably carried out using a solvent selected from ketones, ethers, esters, amides or nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons and water or their mixtures. More preferably, the solvent is selected from C1-C4 alkyl alcohols, esters or their mixtures. Most preferably, the solvent is methanol, ethanol, ethyl acetate or their mixtures.
The conversion is preferably carried out using 0.95 to -1 .05 molar equivalents of the acid. Preferably, the resulting salt is crystallized at a temperature of from -30 °C to the boiling point of the solvent.
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and hydrobromic acid according to the invention has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (XPERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid has the following most characteristic powder diffraction peaks illustrated in Table , below:
Pos. d-spacing Rel. Int.
[°2Th.] [A] [%]
5,63 15,675 9,2
5,83 15, 154 5,6
6,94 12,724 4,5
1 1 ,35 7,791 9,5
1 1 ,74 7,532 34,6
17, 1 1 5, 179 6,6
17,68 5,012 17,0
18,56 4,778 8,2
19,22 4,614 52,4
20,50 4,329 39,3
21 ,62 4,107 29,3
22,49 3,949 10,9
23,30 3,815 10,0
24,46 3,637 100,0
24,73 3,598 25,3
25,66 3,470 14,5
26,07 3,415 12,3
26,68 3,339 13,7
27,02 3,297 12,9
28,96 3,081 12,0
29,51 3,024 20,9
31 , 19 2,865 13,3
32,41 2,760 9,5
33,04 2,709 20,9
34,57 2,593 17,5
35,94 2,497 13,6
37,58 2,391 12,3
Table 1
Preferably, the salt or co-crystal is characterized by the following peaks: 1 1.74; 19.22; 20.50; 24.46° 2Θ ± 0.2° 2Θ., more preferably, 1 1 .74; 17.68; 19.22; 20.50; 21.62; 24.46; 29.51 ; 33.04° 2Θ ± 0.2° 2Θ. The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrobromic acid can be further characterized by thermal analytical methods. Figure 2 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 3 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively. Hydrobromide salt or co-crystal shows a 0.7% weigth loss in the range of 20°C-to 00°C. The DSC measurement gives a melting process with
and TPeak=208.7°C.
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and hydrochloric acid according to the invention has the characteristic XRPD pattern as shown in Figure 4. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid has the following most characteristic powder diffraction peaks illustrated in Table 2, below:
Pos. d-spacing Rel. Int.
[°2Th.] [A] [%]
6,07 14,548 4,9
12,01 7,361 31 ,8
12,89 6,861 1 1 ,8
13,32 6,641 7,9
13,86 6,387 7,0
15,29 5,792 6,6
17,46 5,075 5,6
17,98 4,930 42,8
19,29 4,597 18,7
19,74 4,494 19,0
21 ,66 4,101 14,7
22,13 4,014 13, 1
22,71 3,913 7, 1
23,99 3,707 100,0
24,43 3,641 12,7
25,01 3,558 10,3
26,61 3,348 19,8
27,22 3,273 7,2
27,92 3, 193 8,3
30,07 2,970 34,0
32,66 2,740 9,0
Table 2
Preferably, the salt or co-crystal is characterized by the following peaks: 12.01 ; 17.98; 23.99° 2Θ ± 0.2° 2Θ, more preferably, 12.01 ; 17.98; 19.74; 23.99; 26.61 ; 30.07° 2Θ ± 0.2° 2Θ. The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrochloric acid can be further characterized by thermal analytical methods. Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 6 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C
to 250°C and 20°C to 300°C, respectively. Hydrochloride salt or co-crystal shows a 0.3% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 7. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and methanesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 3, below:
Table 3
Preferably, the salt or co-crystal is characterized by the following peaks: 5.37; 1 1.38; 17.10° 2Θ ± 0.2° 2Θ, more preferably, 5.37; 1 1.38; 14.07; 17.10; 19.27; 21 .99; 23.90° 2Θ ± 0.2° 2Θ.
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and methanesulphonic acid can be further characterized by thermal analytical methods. Figure 8 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 9 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively. Hydrochloride salt or co-crystal shows a 2.5% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with Tpeak, = 96°C,
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and benzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 10. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and benzenesulphonic acid has the following most characteristic powder diffraction peaks illustrated in Table 4, below:
Pos. d-spacing Rel. Int.
[°2Th.] [A] [%]
5,14 17,193 100,0
8,13 10,866 4,2
9,33 9,474 13,6
10,31 8,572 4,0
1 1 ,65 7,589 2,3
13,31 6,647 0,9
14,40 6,145 2,8
16, 12 5,495 1 ,8
17,28 5,129 1 ,7
17,62 5,030 2,0
18,92 4,687 1,6
19,75 4,491 14,0
20,71 4,285 5,7
21,28 4,172 3,7
22,43 3,961 8,3
22,85 3,889 10,2
24,58 3,618 3,8
25,30 3,518 2,1
27,98 3,186 1,5
28,61 3,118 1,7
Table 4
Preferably, the salt or co-crystal is characterized by the following peaks: 5.14; 19.75° 2Θ ± 0.2° 2Θ, more preferably, 5.14; 8.13; 9.33; 14.40; 19.75; 22.85° 2Θ ± 0.2° 2Θ.
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and benzenesulphonic acid can be further characterized by thermal analytical methods. Figure 11 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 12 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively. Hydrochloride salt or co-crystal shows a 0.4% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and fumaric acid according to the invention has the characteristic XRPD pattern as shown in Figure 13. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and fumaric acid has the following most characteristic powder diffraction peaks illustrated in Table 5, below:
Pos. d-spacing Rel. Int.
[°2Th.] [A] [%]
6,79 13,010 54,8
12,34 7, 170 57,2
15,67 5,651 34,5
17,65 5,020 21 ,9
18,59 4,769 26,3
19,64 4,517 21 ,5
20,49 4,332 41 ,5
21 ,24 4, 179 27,5
21 ,96 4,044 37,9
22,60 3,931 100,0
23,41 3,797 41 ,3
24,66 3,607 54,8
25, 18 3,535 94,5
25,82 3,447 15,6
28,00 3,184 18,8
28,51 3, 128 22,5
29,74 3,001 22,4
30,93 2,889 1 1 ,4
34, 19 2,621 10,8
38,86 2,316 7,6
Table 5
Preferably, the salt or co-crystal is characterized by the following peaks: 6.79; 12.34; 22.60° 2Θ ± 0.2° 2Θ, more preferably, 6.79; 12.34; 15.67; 17.65; 19.64; 20.49; 22.60; 25.18° 2Θ ± 0.2° 2Θ. The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and fumaric acid can be further characterized by thermal analytical methods. Figure 14 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 15 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively. Hydrochloride salt or co-crystal
shows a 0.2% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with Tonseu
The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and salicylic acid according to the invention has the characteristic XRPD pattern as shown in Figure 16. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate and salicylic acid has the following most characteristic powder diffraction peaks illustrated in Table 6, below:
Pos. d-spacing Rel. Int.
[°2Th.] [A] [%]
6,93 12,744 21 ,2
1 1 ,45 7,721 7,0
13,17 6,716 3,3
14,57 6,075 1 ,9
15,35 5,768 2,6
16,02 5,529 4,0
17,93 4,942 40,2
19,83 4,475 100,0
20,87 4,253 9, 1
22, 14 4,012 18,6
22,79 3,899 8, 1
25,30 3,517 12,3
25,72. 3,461 17,5
28,42 3, 138 18,9
30,50 2,928 2,6
32,62 2,743 3,5
33,06 2,707 4,6
33,81 2,649 2,8
35,23 2,545 3,2
Table 6
Preferably, the salt or co-crystal is characterized by the following peaks: 6.93; 17.93; 19.83° 2Θ ± 0.2° 2Θ, more preferably, 6.93; 17.93; 19.83; 22.14; 25.72; 28.42° 2Θ ± 0.2° 2Θ. The crystalline salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and salicylic acid can be further characterized by thermal analytical methods. Figure 17 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 18 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 250°C and 20°C to 300°C, respectively. Hydrochloride salt or co-crystal shows a 0.2% weigth loss in the range of 20°C-to 100°C. The DSC measurement
gives a melting process with TOnset, i=90.6°C , Τρβ3κ,ι=94.8°0 and T0nset,2= l 38.8oC,
Tpeak,2=140.6°C . -
It has been found that the most of the novel salts or co-crystals of ethyl N-[2-amino-4- [(4-fluorophenyl)methylamino]phenyl]carbamate of the present invention possess better thermal stability properties compared to the themal stability of the modification A of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate which can be found in the original drug product.
The modification A of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was prepared according to patent US5914425 (Example 2). Comparative thermal stability studies were performed (Table G). In case of thermal stability investigation the samples were stored at a temperature of 80°C and under ambient relative humidity in open condition for 24 hours.
The samples were determined by HPLC at the starting point (t0) and after 24 hours (t24). The amount of the impurities above 0.1 area % were added together. The resulted cumulated impurity values of samples at the end of the stability test (t24) were compared to the cumulated impurity values measured at the starting time (t0) according to the following formula:
. ~\ f„, (Σ.24 impurity) - (∑t0 impurity)
Δ impurity (%) = -=—: :— * 100
^ _i ' (.Lto impurity)
The symbols of the formula above have the following meaning: (Δ∑ impurity) (%) increase in the amount of the cumulative impurity in percentage
(∑to impurity) the amount of the cumulative impurity at the starting time (to)
(∑t24 impurity) the amount of the cumulative impurity at the end of the stability test (t24)
It has been found that the novel salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate of the present invention possess better solubility properties compared to the solubility of the modification A of ethyl N-[2-
amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate which can be found in the original drug product.
The modification A of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was prepared according to patent US5914425. Comparative solubility studies were performed. Saturated solubility in water at 37 °C after 24 hours of agitation was measured by HPLC using calibration.
The following examples provide for a further explanation of the present invention but should not be constued as limiting.
Brief Description of Drawings
Figure 1 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
Figure 2 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
Figure 3 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid.
Figure 4 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid. Figure 5 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid.
Figure 6 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrochloric acid.
Figure 7 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
Figure 8 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
Figure 9 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and methanesulphonic acid.
Figure 10 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid.
Figure 11 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid. Figure 12 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and benzenesulphonic acid.
Figure 13 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
Figure 14 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
Figure 15 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and fumaric acid.
Figure 16 is an XRPD pattern of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid. Figure 17 is a DSC curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid.
Figure 18 is an TGA curve of the salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and salicylic acid.
Examples
Example 1
Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate and hydrobromic acid
500 mg (1 .648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of methanol by heating and 373 pl_ (3.296 mmol) of hydrobromic acid (48%) was added. The solution was stirred at room temperature for about 2 hours and the solvent was completely evaporated. The residue was triturated
with 3 mL ethyl acetate and stirred overnight at room temperature. The resulting suspension was filtered off and dried on air by vacuum at room temperature.
Yield: 654 mg (85.3%)
1H-NMR analysis showed a 1 :1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrobromic acid.
Example 2
Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and hydrochloric acid
500 mg (1.648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of methanol by heating and 143 pL (1.648 mmol) of hydrochloric acid (35%) was added. The solution was stirred at room temperature for about 2 hours and the resulting precipitation was filtered off and dried on air by vacuum at room temperature.
Yield: 350 mg (62.5%)
1H-NMR analysis showed a 1 : 1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and hydrochloric acid.
Example 3
Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyljcarbamate and methanesulphonic acid
500 mg (1 .648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of ethanol by heating and 107 pL (1.648 mmol) of methanesulphonic acid was added. The solution was stirred at room temperature for about 2 hours and the solvent was completely evaporated. The residue was triturated with 3 mL ethyl acetate and stirred overnight at room temperature. The resulting suspension was filtered off and dried on air by vacuum at room temperature.
Yield: 578 mg (87.8%)
1H-NMR analysis showed a 1 : 1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and methanesulphonic acid.
Example 4
Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and benzenesulphonic acid
500 mg (1.648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of methanol by heating and 261 mg (1 .648 mmol) of benzenesulphonic acid was added. The solution was stirred at room temperature for about 2 hours and the solvent was completely evaporated. The residue was triturated with 3 mL ethyl acetate and stirred overnight at room temperature. The resulting suspension was filtered off and dried on air by vacuum at room temperature.
Yield: 589 mg (77.4%)
1 H-NMR analysis showed a 1 : 1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and benzenesulphonic acid.
Example 5 Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and fumaric acid
500 mg (1 .648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of methanol by heating and 191 mg (1 .648 mmol) of fumaric acid was added. The solution was stirred at room temperature for about 2 hours and the solvent was completely evaporated. The residue was triturated with 3 mL ethyl acetate and stirred overnight at room temperature. The resulting suspension was filtered off and dried on air by vacuum at room temperature.
Yield: 309 mg (44.7%)
1 H-NMR analysis showed a 1 : 1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and fumaric acid.
Example 6
Preparation of salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and salicylic acid
500 mg (1.648 mmol) of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate was dissolved in 5 mL of methanol by heating and 228 mg (1 .648 mmol) of salicylic acid was added. The solution was stirred at room temperature for about 2 hours and the solvent was completely evaporated. The residue was triturated with 3 mL ethyl acetate and stirred overnight at room temperature. The resulting suspension was filtered off and dried on air by vacuum at room temperature
Yield: 381 mg (52.4%)
1 H-NMR analysis showed a 1 : 1 stoichiometry of ethyl N-[2-amino-4-[(4-fluorophenyl)- methylamino]phenyl]carbamate and salicylic acid.
Analytical methods and results: Analysis - NMR
Structural characterization was conducted using 1 H-NMR spectroscopy at 250 MHz. Instrument: Bruker Avance 250 Solvent: D6-dimethyl sulfoxide Temperature: 303 K The TMS (tetramethylsilane) signal was used as an internal reference at 0.00 ppm.
Analysis - XRPD (X-Ray Powder Diffractometry)
Diffractograms were obtained with laboratory XPERT PRO MPD PANalytical diffractometer equipped with graphite monochromator, used radiation CuKa (I = 1 .542A).
Generator settings:
- excitation voltage 45 kV
anodic current 40 mA.
Scan description:
- scan type - gonio
- measurement range 2 - 40° 2Θ
- step size 0.01° 2Θ
- time per step: 50s.
Sample were measured as received on Si plate (zero background holder).
Incident beam optics: programmable divergence slits (irradiated length 10 mm), 10 mm mask, 1/4° anti-scatter fixed slit, 0.02 rad soller slits.
Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122°, 0.02 rad soller slits, anti-scatter slit 5.0 mm, Ni filter.
Analysis - DSC (Differential Scanning Calorimetry)
DSC measurements were performed on a Perkin Elmer Pyris 1 DSC. The sample were weighed in aluminium pans and covers (20 μί_) and measured in a nitrogen flow. Investigations were performed in a temperature range of 50°C to 250°C with a heating rate of 10°C/min. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks. The specific heat is given in J/g. The weight sample was about 3 mg.
Analysis - TGA (ThermoGravimetric Analysis)
TGA were performed on a Perkin Elmer "RGA 6.
The samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 25°C to 300°C with a heating rate of 10°C/min.
The weight sample was about 13-18 mg.
Analysis - Thermal stability
Thermal stability experiments were performed in a Memmert vacuum oven.
The samples were weighted in Petri dishes and placed into the oven for 24 hours. The investigations were performed at 80°C and ambient humidity, under atmospheric pressure.
Analysis - Thermodynamic solubility
Thermodynamic solubility experiments were performed in an Eppendorf Thermomixer Comfort shaker.
The samples were weighted in Eppendorf tubes and diluted with 1 mL of water. The investigations were performed at 37°C using an agitation of 900 rpm for 24 hours.
Some of the results of the further characterization of the inventive salts or co-crystals are given in detail in the following tables.
A) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and hydrobromic acid
B) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and hydrochloric acid
C) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and methanesulphonic acid
D) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and benzenesulphonic acid
DSC Tpeak,1 = 52.7°C
TGA 0.4% to 100°C
E) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and fumaric acid
F) Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]- carbamate and salicylic acid
G) Comparative thermal stability and thermodynamic solubility of retigabine Modification A and inventive salts or co-crystals of ethyl N-[2-amino-4-[(4- fluorophenyl)methylamino]phenyl]carbamate (A-F) retigabine
Modification
A
A B C D E F
(according
to
US5914425)
thermal stability
A∑impurity
3250 529 >3500 161 579 >3500 1470 (%)
thermodynamic solubility in water
solubility
0.05 4.05 19.94 2.26 3.26 2.92 0.12
(g/L)
pH 5.18 <1 <1 1 .73 1 .78 1 .96 3.33
Claims
1 . A salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]- phenyl]carbamate and one acid selected from the group consisting of hydrobromic acid, hydrochloric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid and salicylic acid.
2. Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyl]carbamate and hydrobromic acid.
3. Salt or co-crystal according to claim 2 in a crystalline or amorphous form.
4. Salt or co-crystal according to claim 3 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 1 1 .74; 19.22; 20.50; 24.46° 2Θ ± 0.2° 2Θ.
5. Salt or co-crystal according to claim 4 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 1 .74; 17.68; 19.22; 20.50; 21.62; 24.46; 29.51 ; 33.04° 2Θ ± 0.2° 2Θ.
6. Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyl]carbamate and hydrochloric acid.
7. Salt or co-crystal according to claim 6 in a crystalline or amorphous form.
8. Salt or co-crystal according to claim 7 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 12.01 ; 17.98; 23.99° 2Θ ± 0.2° 2Θ.
9. Salt or co-crystal according to claim 8 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 12.01 ; 17.98; 19.74; 23.99; 26.61 ; 30.07° 2Θ ± 0.2° 2Θ.
10. Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyljcarbamate and methanesulphonic acid.
1 1 . Salt or co-crystal according to claim 10 in a crystalline or amorphous form.
12. Salt or co-crystal according to claim 1 1 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 5.37; 1 1 .38; 17.10° 2Θ ± 0.2° 2Θ.
Salt or co-crystal according to claim 12 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 5.37; 1 1.38; 14.07; 17.10; 19.27; 21 .99; 23.90° 2Θ ± 0.2° 2Θ.
Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyljcarbamate and benzenesulphonic acid.
Salt or co-crystal according to claim 14 in a crystalline or amorphous form.
Salt or co-crystal according to claim 15 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 5.14; 19.75° 2Θ ± 0.2° 2Θ.
17. Salt or co-crystal according to claim 16 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 5.14; 8.13; 9.33; 14.40; 19.75; 22.85° 2Θ ± 0.2° 2Θ.
18. Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyl]carbamate and fumaric acid.
19. Salt or co-crystal according to claim 18 in a crystalline or amorphous form.
Salt or co-crystal according to claim 19 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 6.79; 12.34; 22.60° 2Θ ± 0.2° 2Θ.
Salt or co-crystal according to claim 20 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 6.79; 12.34; 15.67; 17.65; 19.64; 20.49; 22.60; 25.18° 2Θ ± 0.2° 2Θ.
Salt or co-crystal of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino] phenyl]carbamate and salicylic acid.
Salt or co-crystal according to claim 22 in a crystalline or amorphous form.
Salt or co-crystal according to claim 23 in a crystalline form exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 6.93; 17.93; 19.83° 2Θ ± 0.2° 2Θ.
Salt or co-crystal according to claim 24 exhibiting the following characteristic peaks in the X-ray powder diffraction pattern: 6.93; 17.93; 19.83; 22.14; 25.72; 28.42° 2Θ ± 0.2° 2Θ.
A method for the production of a retigabine salt or co-crystal defined in any one of claims 1 -25, characterized in that the compound of formula I
is converted to a salt by reaction with an acid selected from the group consisting of hydrobromic, hydrochloric, methanesulphonic, benzenesulphonic, fumaric and salicylic acids.
27. The method according to claim 26, characterized in that the conversion is carried out using a solvent selected from ketones, ethers, esters, amides or nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons and water or their mixtures.
28. The method according to claims 26 or 27, characterized in that the solvent is selected from C-i-C4 alkyl alcohols, esters or their mixtures.
29. The method according to claim 28, characterized in that the solvent is methanol, ethanol, ethyl acetate or their mixtures.
30. The method according to any one of claims 26-29, characterized in that the conversion is carried out using 0.95 to 1 .05 molar equivalents of the acid.
31 . The method according to any one of claims 26-30, characterized in that the resulting salt is crystallized at a temperature of from -30 °C to the boiling point of the solvent.
32. Use of the retigabine salt or co-crystal defined in any one of claims 1 -25 for preparation of a pharmaceutical composition:
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5384330A (en) | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
US5914425A (en) | 1997-01-20 | 1999-06-22 | Asta Medica Aktiengesellschaft | Modifications of 2-amino-4-(4-5fluorobenzylamino)-1-ethoxycarbonylaminobenzene, and processes for their preparation |
WO2010105823A1 (en) | 2009-03-17 | 2010-09-23 | Ratiopharm Gmbh | Solid retigabine in non-crystalline form |
WO2011039369A2 (en) | 2009-10-02 | 2011-04-07 | Medichem S.A. | Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative |
WO2011101456A2 (en) | 2010-02-19 | 2011-08-25 | Medichem S.A. | Stabilized phenylcarbamate derivative in solid state |
-
2012
- 2012-08-09 WO PCT/CZ2012/000077 patent/WO2014023270A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5384330A (en) | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
US5914425A (en) | 1997-01-20 | 1999-06-22 | Asta Medica Aktiengesellschaft | Modifications of 2-amino-4-(4-5fluorobenzylamino)-1-ethoxycarbonylaminobenzene, and processes for their preparation |
WO2010105823A1 (en) | 2009-03-17 | 2010-09-23 | Ratiopharm Gmbh | Solid retigabine in non-crystalline form |
WO2011039369A2 (en) | 2009-10-02 | 2011-04-07 | Medichem S.A. | Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative |
WO2011101456A2 (en) | 2010-02-19 | 2011-08-25 | Medichem S.A. | Stabilized phenylcarbamate derivative in solid state |
Non-Patent Citations (3)
Title |
---|
CNS DRUG REVIEWS, vol. 11, 2005, pages 1 |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ANON.: "Preparation of crystalline salts of ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate", XP002696575, retrieved from STN Database accession no. 2013:87290 * |
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 April 2010 (2010-04-01), XP002696571, retrieved from STN Database accession no. 1215347-18-4 * |
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