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

Definitions

• TAPENTADOL A new solid form of TAPENTADOL and a method of its preparation Technical Field
• the invention relates to a new crystalline form of tapentadol hydrobromide (I), chemically
• US Patent no. 6,344,558 describes a group of l-phenyl-3-dimethylaminopropane compounds, processes of their preparations, their pharmaceutical compositions and methods of application. These compounds are used in pharmaceutical compositions as efficient analgesics. They also include tapentadol hydrochloride as a centrally acting analgesic with a dual mode of action. As an agonist of the ⁇ -opioid receptors it prevents transmission of nerve impulses by the spinal cord and at the same time it prevents reuptake of norepinephrine in synaptic clefts.
• Patent WO 2009/0149634 describes 3 different forms of tapentadol base, a process of their preparation and mentions their characterization using the X-ray powder diffraction.
• US patent application 201 1/071 120 describes preparation and characterization of several salts of tapentadol (camphorsulfonate, dibenzoyltartrate, malate, maleate and salicylate).
• the salts with high-molecular-weight acids e.g. camphorsulfonic acid, dibenzoyltartaric acid and the like
• Other salts may also manifest unsuitable physical-chemical properties such as a low melting point, low solubility in water or chemical or polymorphous instability.
• the invention provides a new crystalline form of tapentadol hydrobromide, characterized by the following characteristic reflections in an X-ray powder pattern measured at 14.6; 15.5; 17.9; 21.1 ; 21.8 ⁇ 0.2° 2-theta, which were measured using the CuKa radiation.
• This form also manifests the following other characteristic reflections: 10.2; 16.9; 24.6; 25.0; 25.4; 28.19; 29.2 and 31 ⁇ 0,2° 2-theta.
• the hydrobromide in accordance with this invention is characterized by the powder XRPD pattern indicated in Table 1 and the crystallographic data indicated in Table 2, which were obtained by X-ray diffraction of a monocrystal.
• Tab. 1 XRPD - characteristic diffraction peaks corresponding to tapentadol hydrobromide
• the hydrochloride of form A is a highly chemically stable compound according to the said document.
• the tapentadol hydrobromide in accordance with our invention is not only equally chemically stable as the known forms, but also considerably less hygroscopic than the described hydrochlorides.
• form B absorbs up to 14% of weight of water at 80% relative humidity
• form A absorbs 10% of water
• our new hydrobromide form absorbs only 2 to 3% of water under the same conditions. This evaluation was made based on measurements using the DVS method, wherein equilibrium hygroscopicity is determined in several sorption and desorption cycles.
• Hygroscopicity is one of the properties which are monitored when suitable candidates for pharmaceutical development are looked for.
• Hygroscopicity i.e. the ability of substances to bind water, plays an important role in the preparation and stability of a dosage form. If a substance only absorbs a small amount of water, it can be employed in a number of processes that are used in pharmaceutical production, for example, it can be used without problems in methods that work with water as a medium, e.g. wet granulation, without its physical-chemical properties being changed during the processing.
• Another aspect of this invention provides a method of preparation of tapentadol hydrobromide.
• the hydrobromide is prepared from the free base of tapentadol in a suitable solvent by treatment with hydrobromic acid or hydrogen bromide, which may be either in the gaseous state or as a solution in an organic solvent.
• the resulting hydrobromide either directly crystallizes from the solution or the resulting solution is concentrated and/or another solvent is added as an antisolvent.
• the tapentadol base is dissolved in a solvent, which is, e.g., a C 3 -C 5 ketone, Q-Q alcohol, an acetic acid ester with a Q-C4 alcohol, tert- butyl methyl ether, tetrahydrofuran or dioxane, hydrobromic acid is added in an amount of 0.9 to 1.1 equivalents, or a solution of hydrobromic acid in a C to C 4 alcohol is used.
• a solvent which is, e.g., a C 3 -C 5 ketone, Q-Q alcohol, an acetic acid ester with a Q-C4 alcohol, tert- butyl methyl ether, tetrahydrofuran or dioxane
• hydrobromic acid is added in an amount of 0.9 to 1.1 equivalents, or a solution of hydrobromic acid in a C to C 4 alcohol is used.
• the resulting solution is cooled to a temperature in the range of 0 to 40°C and possibly another solvent is added as an antisolvent, which is, e.g., diethyl ether, tert-butyl methyl ether, ethyl acetate or diisopropyl ether.
• an antisolvent which is, e.g., diethyl ether, tert-butyl methyl ether, ethyl acetate or diisopropyl ether.
• the crystallized hydrobromide is then isolated using known techniques.
• the crystalline tapentadol hydrobromide is a chemically polymorphously stable form with a high melting point (183-185°C), which is preferred as compared to tapentadol hydrochloride form A, which manifests a polymorphous transformation at a relatively low temperature of ca. 45°C.
• solubility of the solid form of the active substance in water is Another criterion that should be considered. This parameter was measured by adding a charge of the substance into 1 ml of water at 25°C,
• tapentadol hydrobromide 0.25 g/ml tapentadol hydrochloride form A: > 0.4 g/ml (the form in the Palexia product made by Gruenenthal)
• Tapentadol hydrobromide in accordance with our invention exhibits sufficiently high solubility in water for the active substance to be biologically available. Compared to tapentadol hydrochloride form A, which shows very good solubility in water, the relatively lower solubility of tapentadol hydrobromide may be convenient for, e.g., the preparation of a dosage form with extended release (Handbook of Pharmaceutical Salts, Wiley, 201 1, Chapter 4).
• Fig. 1 XRPD record for tapentadol hydrobromide
• Fig. 2 DSC record for tapentadol hydrobromide
• Fig. 4 DSC record for tapentadol hydrochloride, Form A
• Fig. 5 DVS record for tapentadol hydrochloride, Form A
• Fig. 6 DSC record for tapentadol hydrochloride, Form B
• Fig. 7 DVS record for tapentadol hydrochloride, Form B
• Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used.
• the Differential Scanning Calorimetry (DSC) records were measured with a DSC Pyris 1 device made by Perkin Elmer. The charge of the sample in a standard Al pot was between 3-4 mg and the heating-up rate was 10°C/min.
• the temperature program used consists of 1 minute of stabilization at the temperature of 50°C and then of heating to 250°C at the heating-up rate of 10°C/min.
• As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
• the Dynamic Vapour Sorption (DVS) records were measured with a DVS Advantage 1 device made by Surface Measurement Systems.
• the charge of the sample in a quartz dish was between 15-30 mg and the temperature in the device was 25-25.2°C.
• Measurement program used the sample was loaded with two cycles with the course from the relative humidity of 0% to 90% (sorption) and then from 90% to 0% of RH (desorption). This course was repeated in the second cycle. As the carrier gas 4.0 N 2 was used at the flow of 200 seem.
• tapentadol hydrochloride form A and hydrochloride form B were prepared in accordance with the methods described in US 2007/0213405.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2013
  • 2013-02-18 WO PCT/CZ2013/000016 patent/WO2013120466A1/fr not_active Ceased

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