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 preparation

Info

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Withdrawn
Application number
EP15710419.1A
Other languages
German (de)
English (en)
French (fr)
Inventor
Josef Cerny
Ondrej Dammer
Tomas Pekarek
Pavel CALTA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3102560A1 publication Critical patent/EP3102560A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46Compounds 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
    • C07C215/48Compounds 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
    • C07C215/54Compounds 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13Dicarboxylic acids
    • C07C57/145Maleic acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP15710419.1A 2014-02-04 2015-01-30 A solid form of tapentadol maleate and a method of its preparation Withdrawn EP3102560A1 (en)

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

Publications (1)

Publication Number Publication Date
EP3102560A1 true EP3102560A1 (en) 2016-12-14

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ID=52686034

Family Applications (1)

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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

Country Status (4)

Country Link
EP (1) EP3102560A1 (cs)
CZ (1) CZ307492B6 (cs)
EA (1) EA031198B1 (cs)
WO (1) WO2015117576A1 (cs)

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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
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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
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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

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Also Published As

Publication number Publication date
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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