EP3102560A1 - A solid form of tapentadol maleate and a method of its preparation - Google Patents
A solid form of tapentadol maleate and a method of its preparationInfo
- Publication number
- EP3102560A1 EP3102560A1 EP15710419.1A EP15710419A EP3102560A1 EP 3102560 A1 EP3102560 A1 EP 3102560A1 EP 15710419 A EP15710419 A EP 15710419A EP 3102560 A1 EP3102560 A1 EP 3102560A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tapentadol
- solution
- mtbe
- maleate
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229960005126 tapentadol Drugs 0.000 title claims abstract description 67
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 title claims description 58
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims description 39
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims description 39
- 238000000034 method Methods 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 title claims description 15
- 239000007787 solid Substances 0.000 title description 2
- 238000000113 differential scanning calorimetry Methods 0.000 claims abstract description 10
- 238000002329 infrared spectrum Methods 0.000 claims abstract description 4
- 238000010521 absorption reaction Methods 0.000 claims abstract description 3
- 230000005855 radiation Effects 0.000 claims abstract description 3
- 229910016523 CuKa Inorganic materials 0.000 claims abstract 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- 239000011976 maleic acid Substances 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 238000002955 isolation Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 238000010533 azeotropic distillation Methods 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- IMCMKXGGFQJPLF-YECZQDJWSA-N 3-[(2r,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrobromide Chemical compound Br.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 IMCMKXGGFQJPLF-YECZQDJWSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000011081 inoculation Methods 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 3
- 229960001860 salicylate Drugs 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910052925 anhydrite Inorganic materials 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 14
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 13
- ZELFLGGRLLOERW-YECZQDJWSA-N 3-[(2r,3r)-1-(dimethylamino)-2-methylpentan-3-yl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 ZELFLGGRLLOERW-YECZQDJWSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229960004143 tapentadol hydrochloride Drugs 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000002054 inoculum Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- -1 hydrochloric Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- OCQAXYHNMWVLRH-UHFFFAOYSA-N 2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical class C=1C=CC=CC=1C(=O)C(O)(C(O)=O)C(O)(C(=O)O)C(=O)C1=CC=CC=C1 OCQAXYHNMWVLRH-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NTBIYBAYFBNTCD-UHFFFAOYSA-N dibenzoyl 2,3-dihydroxybutanedioate Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C(O)C(O)C(=O)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000005284 excitation Effects 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000018405 transmission of nerve impulse Effects 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
- C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- 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
- C07B2200/07—Optical isomers
Definitions
- the invention relates to a new crystalline form of tapentadol maleate (I), chemically
- the patent EP 0 693 475 deals with a group of l-phenyl-3-dimethylpropane compounds, processes of their preparation, their pharmaceutical compositions and methods of use. These compounds are used in pharmaceutical compositions as efficient analgesics. They also include tapentadol hydrochloride, as a centrally acting analgesic with a dual mechanism of action. As an agonist of ⁇ -opioid receptors, it prevents transmission of nerve impulses along the spinal cord and at the same time inhibits reuptake of noradrenaline in synaptic clefts.
- the patent EP 0 693 475 mentions the possibility of production of pharmaceutically acceptable salts of tapentadol and of similar compounds with suitable acids (such as hydrochloric, hydrobromic, sulphuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric acids etc.).
- suitable acids such as hydrochloric, hydrobromic, sulphuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric acids etc.
- polymorph A is characterized by X-ray powder diffraction therein, polymorph A being defined as the more stable one of the two forms.
- Other documents demonstrate preparation and possibly characterization methods of other polymorphs of tapentadol hydrochloride: CN102924303 (Form C), CN103254088 (Form D) and CN103193659 (an unnamed form).
- the document US2010272815 also describes an amorphous form of tapentadol hydrochloride, similarly to the patent application.
- the patent application WO2009071310 describes 3 different forms of tapentadol base, a process of their preparation and mentions their characterization by means of X-ray powder diffraction.
- Polymorphism occurrence of different crystalline forms, is the property of some molecules and molecular complexes. It is generally known that various salts or polymorphs of pharmaceutically active substances may have different physico-chemical, and consequently pharmacological properties. Then, such salts and their polymorphs can be used to obtain an ideal composition of pharmaceutical formulations containing the given active substance or its salt. This means that it is very important to keep looking for suitable salts or polymorphic forms of pharmaceutically active substances. Discovering new salts and polymorphic forms of tapentadol may provide new methods of improving the characteristics of tapentadol as the active pharmaceutical component of formulations.
- the invention provides a novel crystalline Form A of tapentadol maleate of formula I and a method of its preparation.
- the preparation method of Form A of tapentadol maleate of formula I comprises the following steps: a) preparation of a solution of tapentadol base in ethereal solvents by dissolving tapentadol base in ethereal solvents, or by neutralization of a suitable salt of tapentadol in ethereal solvents by addition of a solution of an inorganic base, and optional drying of the resulting solution by means of azeotropic distillation or by drying with the use of suitable reagents
- step a) adding crystallization inocula of tapentadol maleate Form A, cooling the obtained solution, crystal growth, cooling to the isolation temperature and isolation
- a solution of tapentadol base in suitable ethereal solvents in step a) can be obtained in two ways.
- the first one is direct dissolution of tapentadol base in ethereal solvents such as THF, 2- methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), preferably in tert-butyl methyl ether.
- ethereal solvents such as THF, 2- methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), preferably in tert-butyl methyl ether.
- the other method consists in dissolution or suspension of a suitable tapentadol salt in ethereal solvents and neutralization of the solution/suspension by adding an aqueous solution of an inorganic base.
- Suitable salts include especially hydrobromide, oxalate or salicylate; hydrochloride can be conveniently used.
- Suitable ethereal solvents include especially THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), tert-butyl methyl ether being preferred.
- Suitable inorganic bases include especially LiOH, NaOH, OH, K 2 C0 3 , Na 2 C0 3 , NaHC0 3 , and KHCO 3 ; in a preferred embodiment NaOH is used.
- the solution obtained this way in step a) contains less than 1% of water (by weight, Karl Fischer); preferably less than 0.5% of water (Karl Fischer). If the solution obtained this way contains more than 0.5% by weight of water, it can be dried using a suitable desiccant such as Na 2 S0 , MgS0 ,CaCl 2 , CaSC or with the use of molecular sieves or by removing the azeotropic mixture of TBE/water by azeotropic distillation to keep the water content below 0.5% by weight. It has been surprisingly found out that a content of water higher than 0.5% by weight affects both the yield and isolation (oil formation) or tapentadol maleate.
- a suitable desiccant such as Na 2 S0 , MgS0 ,CaCl 2 , CaSC or with the use of molecular sieves or by removing the azeotropic mixture of TBE/water by azeotropic distillation to keep the water content below 0.5% by weight.
- the tapentadol base solution obtained in step a) contains 2 to 9 mrnol, 0.5 to 2 g, of the tapentadol base in 4 ml of an ethereal solvent, preferably 0.5 to 1,2 g of tapentadol base dissolved in 4 ml of MTBE, with the total water content below 0.5% by weight.
- the tapentadol base solution with a water content below 0.5% by weight obtained this way is, in step b), heated up to a temperature higher than 50°C and a solution of maleic acid in a suitable alcohol starts to be added to the solution.
- the addition speed is selected such that the internal temperature of the mixture solution does not drop below 40°C.
- Suitable alcohols include especially methanol, ethanol, n-propanol, isopropanol or tert-butanol, isopropanol being used in a preferred embodiment.
- a necessary precondition for the subsequent crystallization is that after completion of addition of the maleic acid solution a clear single-phase solution is obtained. This can be achieved just by suitable temperature selection (above 40°C) and the solvents/tapentadol base ratio. Maleic acid is added approximately in the ratio of 1 to 1.5 equivalents related to the tapentadol base, preferably 1 to 1.1 equivalents.
- step c inoculated by addition of 0.5 to 2% by weight of tapentadol maleate Form A at 40 ⁇ 5°C.
- 1% of tapentadol maleate Form A is used.
- the inoculation has an essential influence on product isolation.
- To obtain tapentadol maleate of form I a single-phase solution has to be inoculated, otherwise there is a risk of obtaining a semi-crystalline or oily form of the product.
- the suitably inoculated reaction mixture is then cooled down to 30 to 40°C and is kept at this temperature for at least 0.5 hours. In a preferred embodiment this is 35 ⁇ 1°C. This procedure supports formation of crystalline particles with convenient properties (good filterability, a product that can be dried well).
- This invention further provides Form A of tapentadol maleate of formula I, characterized with the X-ray powder diffraction pattern shown in Figure 1.
- Table 1 contains the diffraction peaks of this form. Its characteristic reflections are as follows: 11.6; 17.1; 20.4; 24.2 and 25,9 ⁇ 0,2° 2-theta.
- Form A obtained this way is suitable for pharmaceutical application.
- This form of tapentadol maleate is very stable at a humidity up to 80% and is very well soluble with a high dissolution rate, which are suitable conditions for using the compound for formulation of the final dosage form.
- Tapentadol maleate Form A of formula I in accordance with this invention is characterized by the XRPD pattern presented in Table 1.
- Tapentadol maleate of formula I was measured with Differential Scanning Calorimetry (DSC) and exhibits the main onset temperature of 90.0°C (see Fig. 2).
- Tapentadol maleate of formula I is characterized by the following absorption peaks in the IR spectrum: 3217, 2971, 2874, 1705, 1619, 1587, 1534, 1484, 1351, 1250, 1188 a 1075 cm “1 (see Fig. 3). Brief Description of Figures
- Fig. 1 XRPD pattern of Form A of tapentadol maleate of formula I
- Fig. 2 DSC pattern of Form A of tapentadol maleate of formula I
- a flat powder sample was used that was placed on a Si plate.
- IR Spectroscopy For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used. Measuring parameters of IR Spectroscopy: The spectra were measured using a FTIR Nicolet Nexus device (Thermo, USA). Each spectrum was obtained by taking 64 scans in the resolution of 2 cm "1 . The records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device from Perkin Elmer. The sample charge in a standard Al pot was between 3-4 mg and the heating rate was 5°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 50°C and then of heating up to 250°C at the heating rate of 10°C/min. As the carrier gas 4.0 N 2 was used at the flow rate of 20 ml/min.
- Tapentadol base (5.2 g; 23.5 mmol) is dissolved in 20.8 ml of tert. butyl methyl ether and the solution is heated up to boiling.
- a previously prepared solution of maleic acid (2.73 g; 23.5 mmol) in 18 ml of isopropyl alcohol is added to the solution dropwise under boiling.
- the resulting solution is cooled down to the temperature of 40°C and an inoculum of tapentadol maleate Form A (0.052 g) is added. Then, the mixture is cooled down to 35°C and agitated for 1 hour. The resulting suspension is cooled down to -10°C.
- Tapentadol hydrochloride (6 kg; 23.3 mol) is suspended in 43 1 of tm-butyl methyl ether.
- An aqueous solution of NaOH (980 g in 10 1) is added to the suspension and the reaction mixture is vigorously agitated for 30 minutes.
- the aqueous phase is separated and the organic phase is washed with 10 1 of water.
- 14 1 of a distillate is removed from the reaction mixture by distillation. Then, distillation is continued, with continual addition of dry tert-butyl methyl ether (26 1), at such a rate that a constant volume in the reaction mixture is maintained.
- the temperature of the solution is adjusted to 50°C and a solution of maleic acid (2.7 kg; 23.3 mol) in 13.5 1 of isopropanol is added.
- the reaction mixture is cooled down to the temperature of 40°C and an inoculum of tapentadol maleate Form A (60 g) is added.
- the mixture is cooled down to 35°C and agitated for 1 hour.
- the resulting suspension is cooled down to - 10°C.
- the separated substance is aspirated and washed with 6.5 1 of a mixture of ferf-butyl methyl ether/isopropanol (3/1).
- the final product is then dried in a vacuum drier at 40°C. 7.0 g (90% by weight of the theoretical amount) of tapentadol maleate of crystalline Form A corresponding to the XRPD record presented in Fig. 1 and DSC shown in Fig. 2 was obtained.
- Tapentadol hydrobromide 300 kg; 1 mol is suspended in 1.8 1 of ieri-butyl methyl ether.
- An aqueous solution of NaOH 42 g in 450 1 is added to the suspension and the reaction mixture is vigorously agitated for 30 minutes.
- the aqueous phase is separated and the organic phase is washed with 2 x 450 ml of water.
- 600 ml of a distillate is removed from the reaction mixture by distillation. Then, distillation is continued, with continual addition of dry tert-butyl methyl ether (1000 ml), at such a rate that a constant volume in the reaction mixture is maintained.
- the temperature of the solution is adjusted to 50°C and a solution of maleic acid (115 kg; 1 mol) in 580 ml of isopropanol is added.
- the reaction mixture is cooled down to 40°C and an inoculum of tapentadol maleate Form A is added.
- the mixture is cooled down to 35°C and agitated for 1 hour.
- the resulting suspension is cooled down to -10°C.
- the separated substance is aspirated and washed with a minimal amount of a mixture of tert-butyl methyl ether/isopropanol (3/1).
- the final product is then dried in a vacuum drier at 40°C.
- 305 g (91% by weight of the theoretical amount) of tapentadol maleate of crystalline Form A corresponding to the XRPD record presented in Fig. 1 and DSC shown in Fig. 2 was obtained.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ2014-79A CZ307492B6 (cs) | 2014-02-04 | 2014-02-04 | Pevná forma maleátu tapentadolu a způsob její přípravy |
PCT/CZ2015/000011 WO2015117576A1 (en) | 2014-02-04 | 2015-01-30 | A solid form of tapentadol maleate and a method of its preparation |
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EP3102560A1 true EP3102560A1 (en) | 2016-12-14 |
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Application Number | Title | Priority Date | Filing Date |
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EP15710419.1A Withdrawn EP3102560A1 (en) | 2014-02-04 | 2015-01-30 | A solid form of tapentadol maleate and a method of its preparation |
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Country | Link |
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EP (1) | EP3102560A1 (cs) |
CZ (1) | CZ307492B6 (cs) |
EA (1) | EA031198B1 (cs) |
WO (1) | WO2015117576A1 (cs) |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4426245A1 (de) | 1994-07-23 | 1996-02-22 | Gruenenthal Gmbh | 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung |
DE10326097A1 (de) | 2003-06-06 | 2005-01-05 | Grünenthal GmbH | Verfahren zur Herstellung von Dimethyl-(3-aryl-butyl)-aminverbindungen |
DE10328316A1 (de) | 2003-06-23 | 2005-01-20 | Grünenthal GmbH | Verfahren zur Herstellung von Dimethyl-(3-aryl-buthyl)-aminverbindungen als pharmazeutische Wirkstoffe |
DE602004007905T2 (de) | 2004-06-28 | 2008-05-08 | Grünenthal GmbH | Kristalline Formen von (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochlorid |
DE602007004494D1 (de) | 2006-07-24 | 2010-03-11 | Janssen Pharmaceutica Nv | Herstellung von (2r,3r)-3-(3-methoxyphenyl)-n,n,2- trimethylpentanamin |
TWI496762B (zh) | 2006-07-24 | 2015-08-21 | 製備(1r,2r)-3-(3-二甲胺基-1-乙基-2-甲基-丙基)-酚之方法 | |
TWI401237B (zh) | 2006-07-24 | 2013-07-11 | 3-〔(1r,2r)-3-(二甲基氨基)-1-乙基-2-甲基丙基〕酚之製備 | |
HUE031126T2 (en) | 2007-12-07 | 2017-07-28 | Gruenenthal Gmbh | Crystalline modifications of (1R, 2R) -3- (3-Dimethylamino-1-ethyl-2-methylpropyl) phenol |
US20100272815A1 (en) | 2009-04-28 | 2010-10-28 | Actavis Group Ptc Ehf | Amorphous form of tapentadol hydrochloride |
CN102002065B (zh) | 2009-09-02 | 2014-09-10 | 上海特化医药科技有限公司 | 他喷他多的制备方法及其中间体 |
US8288592B2 (en) * | 2009-09-22 | 2012-10-16 | Actavis Group Ptc Ehf | Solid state forms of tapentadol salts |
CA2785035A1 (en) | 2009-12-29 | 2011-07-07 | Mapi Pharma Limited | Intermediate compounds and processes for the preparation of tapentadol and related compounds |
EP2582659B1 (en) | 2010-06-15 | 2015-03-11 | Grünenthal GmbH | Process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds |
IT1401109B1 (it) | 2010-07-02 | 2013-07-12 | Archimica Srl | Nuovo processo per la preparazione di tapentadol e suoi intermedi. |
US9133142B2 (en) | 2010-07-23 | 2015-09-15 | Gruenenthal Gmbh | Salts or co-crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol |
WO2012051246A1 (en) | 2010-10-12 | 2012-04-19 | Ratiopharm Gmbh | Tapentadol hydrobromide and crystalline forms thereof |
CZ302992B6 (cs) | 2010-12-30 | 2012-02-08 | Zentiva, K.S. | Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu (tapentadolu) |
WO2013105109A1 (en) | 2011-11-09 | 2013-07-18 | Indoco Remedies Limited | Process for the preparation of tapentadol |
CN102924303B (zh) | 2012-10-31 | 2013-11-20 | 合肥市新星医药化工有限公司 | 盐酸他喷他多晶型c及其制备方法和应用 |
CN103193659A (zh) | 2013-03-15 | 2013-07-10 | 北京润德康医药技术有限公司 | (-)-(1r,2r)-3-(3-二甲基氨基-1-乙基-2甲基丙基)苯酚盐酸盐新晶型及其制备方法 |
CN103254088B (zh) | 2013-05-24 | 2014-08-06 | 合肥市新星医药化工有限公司 | 盐酸他喷他多晶型d及其制备方法和应用 |
-
2014
- 2014-02-04 CZ CZ2014-79A patent/CZ307492B6/cs not_active IP Right Cessation
-
2015
- 2015-01-30 EA EA201691559A patent/EA031198B1/ru not_active IP Right Cessation
- 2015-01-30 EP EP15710419.1A patent/EP3102560A1/en not_active Withdrawn
- 2015-01-30 WO PCT/CZ2015/000011 patent/WO2015117576A1/en active Application Filing
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Also Published As
Publication number | Publication date |
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CZ201479A3 (cs) | 2015-08-12 |
EA031198B1 (ru) | 2018-11-30 |
EA201691559A1 (ru) | 2016-12-30 |
CZ307492B6 (cs) | 2018-10-17 |
WO2015117576A1 (en) | 2015-08-13 |
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