EA031198B1

EA031198B1 - Solid form of tapentadol maleate and method of its preparation

Info

Publication number: EA031198B1
Application number: EA201691559A
Authority: EA
Inventors: Йосеф Церны; Ондрей Даммер; Томаш Пекарек; Павел Цальта
Original assignee: Зентива, К.С.
Priority date: 2014-02-04
Filing date: 2015-01-30
Publication date: 2018-11-30
Also published as: EA201691559A1; EP3102560A1; WO2015117576A1; CZ307492B6; CZ201479A3

Abstract

The present solution relates to tapentadol maleate Form A of formula I, exhibiting the following characteristic reflections in an X-ray powder diffraction pattern, measured with the use of CuKα radiation: 10.7; 11.6; 16.0; 17.1; 20.4; 24.2 and 25.9±0.2° 2-theta, the main onset temperature of 90.0°C when measured with the use of Differential Scanning Calorimetry (DSC), and the absorption peaks at 3217, 2971, 2874, 1705, 1619, 1587, 1534, 1484, 1351, 1250, 1188 a 1075 cmin the IR spectrum.

Description

The invention relates to a new crystalline form of tapentadol maleate (I), according to chemical nomenclature 3 - [(1K, 2K) -3- (dimethylamino) -1-ethyl-2-methylpropyl] phenol maleate, and the method of its production

Prior art

EP 0693475 describes a group of 1-phenyl-3-dimethylpropane compounds, methods for their preparation, their pharmaceutical compositions and methods for their use. These compounds are used in pharmaceutical compositions as effective analgesics. They also include tapentadol hydrochloride as a centrally acting analgesic with a dual mechanism of action. As an agonist of the mu-opioid receptors, it prevents the transmission of nerve impulses along the spinal cord and at the same time inhibits the reuptake of norepinephrine in synaptic clefts.

Various methods for preparing tapentadol, its optical isomers and pharmaceutically acceptable salts are described in a number of patents or patent applications, for example, US Pat. No. 6,248,737 and US Pat. 2011157390, WO 20111026314, WO 2013105109, WO 2012089177, as well as in a number of others.

In the patent EP 0693475 mentioned the possibility of obtaining pharmaceutically acceptable salts of tapentadol and similar compounds with suitable acids (such as hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, amber, tartaric, almond, fumaric, lactic, citric acid, etc. .). However, from the whole spectrum of the proposed salts, only crystalline hydrochloride was obtained, isolated and described in sufficient detail. The polymorph of tapentadol hydrochloride, thus isolated, was identified as Form B.

WO 2006000441 describes two crystalline forms of hydrochloride: the above Form B and Form A. Each of the polymorphs was characterized by X-ray powder diffraction, polymorph A was determined to be the more stable of the two forms. Other documents demonstrate the preparation and possible methods for determining the characteristics of other polymorphs of tapentadol hydrochloride: CN 102924303 (form C), CN 103254088 (form D) and CN 103193659 (unnamed form). The document US 2010272815 also describes the amorphous form of tapentadol hydrochloride in a manner similar to that of a patent application. Patent application WO 2009071310 describes 3 different forms of the base of tapentadol, a method for their preparation and their characterization using X-ray powder diffraction. Two other polymorphic forms of the free base of tapentadol are also described in the application WO 2012001571. A wide range of salts and co-crystals are described in the application WO 2012010316. However, most forms were not physically characterized in any way and no specific method for their preparation was mentioned. . The specific form of tapentadol hydrobromide has also been described in WO 2012051246.

The document US 20110071120 describes the preparation and characterization of several salts of tapentadol (camphor sulfonate, dibenzoyl tartrate, malate and salicylate). However, salts of high molecular weight acids (for example camphorsulfonic acid, dibenzoyl tartaric acid, and the like) are not suitable for pharmaceutical use, as they may unacceptably increase the size of the dosage form (Handbook of Pharmaceutical Salts, Wiley, 2011, Chapter 7). This problem must be taken into account, especially in the case of tapentadol, since commercially available dosage forms contain from 50 to 250 mg of tapentadol (in the form of hydrochloride). This document also mentions tapentadol maleate, characterized only by XRPD (X-ray powder diffraction), which was obtained with a very low yield.

Polymorphism, the emergence of various crystalline forms, is a property of some molecules and molecular complexes. It is well known that various salts or polymorphs of pharmaceutically active substances can have different physicochemical and, therefore, pharmacological properties. Thus, such salts and their polymorphs can be used to obtain the ideal composition of pharmaceutical preparations containing this active substance or its salt. This means that it is very important to continue the search for suitable salts or polymorphic forms of pharmaceutically active substances. The discovery of new salts and polymorphic forms of tapentadol can provide new ways to improve the characteristics of tapentadol as an active pharmaceutical component of preparations.

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Description of the invention

The invention relates to a new crystalline Form A of tapentadol maleate of formula I and a method for its preparation. The process for preparing Form A of tapentadol maleate of formula I comprises the following steps:

a) preparing a solution of tapentadol base in ethereal solvents by dissolving the base of tapentadol in ethereal solvents or neutralizing a suitable salt of tapentadol in ethereal solvents by adding an inorganic base solution, and optionally drying the resulting solution by azeotropic distillation or by drying using suitable reagents,

b) heating the resulting solution and adding dropwise a solution of maleic acid dissolved in alcohol,

c) adding a crystallization seed of Form A of tapentadol maleate, cooling the resulting solution, growing crystals, cooling to a temperature of selection and selection.

A solution of the base of tapentadol in suitable ether solvents in step a) can be obtained in two ways. The first is direct dissolution of the base of tapentadol in an ether solvent such as THF (tetrahydrofuran), 2-methyltetrahydrofuran (2-Me-THF), cyclopentylmethyl ether and tert-butylmethyl ether (MTBE), preferably in tert-butylmethyl ether. Another way is to dissolve or suspend a suitable salt of tapentadol in ethereal solvents and neutralize the solution / suspension by adding an aqueous solution of an inorganic base. Suitable salts include in particular hydrobromide, oxalate or salicylate; Hydrochloride may conveniently be used. Suitable ether solvents include, in particular, THF, 2-methyltetrahydrofuran (2-Me-THF), cyclopentyl methyl ether and tert-butyl methyl ether (MTBE), with tert-butyl methyl ether being preferred. Suitable inorganic bases include in particular LiOH, NaOH, KOH, K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO _3, and KHCO ₃ ; in a preferred embodiment, NaOH is used.

The solution thus obtained in step a) contains less than 1% by weight of water (according to Karl Fischer); preferably less than 0.5% by weight of water (according to Karl Fischer). If the solution thus obtained contains more than 0.5% by weight of water, it can be dried using a suitable desiccant such as Na ₂ SO ₄ , MgSO ₄ , CaCl ₂ , CaSO ₄ , or using molecular sieves, or remove the azeotropic mixture of MTBE / water by azeotropic distillation in order to keep the water content less than 0.5 wt.%. Unexpectedly, it was found that the water content of more than 0.5 wt.% Affects both the yield and the release (formation of oil) of tapentadol maleate.

The solution of the base of tapentadol obtained in stage a) contains from 2 to 9 mmol, from 0.5 to 2 g of the base of tapentadol in 4 ml of ether solvent, preferably from 0.5 to 1.2 g of the base of tapentadol dissolved in 4 ml of MTBE , with a total water content below 0.5% by weight. The solution of tapentadol base with a water content of less than 0.5 wt.% Thus obtained is heated in step b) to a temperature above 50 ° C and a solution of maleic acid in a suitable alcohol is added to the solution. The rate of addition is chosen so that the internal temperature of the mixture solution does not fall below 40 ° C. Suitable alcohols include in particular methanol, ethanol, n-propanol, isopropanol or tert-butanol, isopropanol is used in a preferred embodiment. A prerequisite for the subsequent crystallization is that after completion of the addition of the maleic acid solution, a clear single-phase solution is obtained. This can only be achieved by appropriate selection of temperature (above 40 ° C) and the ratio of solvents / base tapentadol. Maleic acid is added approximately in a ratio of from 1 to 1.5 eq. in relation to the base of tapentadol, preferably from 1 to 1.1 eq. In the most preferred embodiment, 0.53 g of maleic acid in 2.5 to 3.5 ml of isopropyl alcohol are added to 0.9 to 1.1 g of the base of tapentadol dissolved in 4 ml of MTBE, while the temperature is maintained in the range from 50 to 55 ° C.

The solution thus obtained is seeded in step c) by adding 0.5 to 2% by weight of Form A of tapentadol maleate at 40 ± 5 ° C. In a preferred embodiment, 1% by weight of Form A of tapentadol maleate is used. Persecution has a significant effect on product release. To obtain tapentadol maleate form I, a single-phase solution must be persecuted, otherwise there is a risk of obtaining a semi-crystalline or oily form of the product. Accordingly, the seeded reaction mixture is cooled to a temperature of from 30 to 40 ° C and maintained at this temperature for at least 0.5 h. In a preferred embodiment, this is 35 ± 1 ° C. This procedure promotes the formation of crystalline particles with suitable properties (good filterability, a product that can be well dried).

This is followed by cooling to a temperature of excretion in the range from 0 to -20 ° C, preferably to a temperature of -10 ± 1 ° C, and isolation of the product. The product is washed with ether-alcohol, preferably MTBE-isopropyl alcohol, and dried. The term temperature referred to in the examples, the claims and the description, always refers to the internal temperature of the mixture, solution or suspension.

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This invention additionally provides Form A of tapentadol maleate of formula I, characterized by an x-ray powder diffractogram shown in FIG. 1. The table shows the diffraction peaks of this form. Its characteristic peaks at a 2-theta reflection angle are: 11.6; 17.1; 20.4; 24.2 and 25.9 ± 0.2 °.

Form A thus obtained is suitable for pharmaceutical applications. This form of tapentadol maleate is very stable at a relative air humidity of up to 80% and is very soluble with a high dissolution rate, which is suitable conditions for using the compound to prepare the final dosage form.

Form A of tapentadol maleate of formula I in accordance with the present invention is characterized by the XRPD diffractogram presented in the table.

XRPD — Characteristic Diffraction Peaks of Form A of Tapentadol Maleate of Formula I

Pos. [° 2teta] interatomic distance [A] Rel. int-th. [%] 10.67 8.285 19.2 10.93 8,087 12.4 11.65 7.591 30.4 12.89 6,865 11.7 13.11 6,748 6.8 14.43 6.133 11.6 15.41 5,744 12.8 16.01 5,530 18,8 17,10 5.182 100.0 17.99 4,928 23.0 18.41 4,815 8.0 18.87 4,699 13.5 19.23 4.613 7.5 20.40 4.349 34.0 21.46 4.137 21.7 22.66 3,920 10.1 24.16 3,681 57.9 25.85 3,443 39.9 28.64 3.114 7.4 28.96 3,081 8.3 29.19 3,057 7.5 29.79 2,997 5.9 30.75 2,905 8.7 32.48 2,754 4.8 36.50 2.460 4.8 37.81 2.377 3.6

Tapentadol maleate of formula I was measured using differential scanning calorimetry (DSC), and a baseline decomposition start temperature of 90.0 ° C was obtained (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 and 1075 cm (see Fig. 3).

Brief description of the figures

FIG. 1 - XRPD diffractogram of Form A of tapentadol maleate of formula I.

FIG. 2 - DSC thermogram of Form A of tapentadol maleate of formula I.

FIG. 3 - IR spectrum of Form A of tapentadol maleate of formula I.

Examples

The samples in the examples below are characterized using X-ray powder diffraction (XRPD), IR spectroscopy and differential scanning calorimetry (DSC) methods.

XRPD measurement parameters: Diffraction patterns were obtained using a X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, used CuKa radiation (λ = 0.1547 nm (1542 A)), excitation voltage: 45 kV, anode current: 40 mA, measurement range: 2 - 40 ° 2θ, pitch: 0.01 ° 2θ. For the measurement, a flat sample of powder was used, which was placed on a Si plate. To set the primary optical equipment using programmable divergence slit with the irradiated specimen area of 10 mm, 0.02 rad Soller slit and ^{a _1/4} anti-diffusion gap. The X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slit and 5.0 mm anti-diffusion slit was used to install the secondary optical equipment.

Measurement parameters of IR spectroscopy: spectra were obtained using an FTIR Nicolet Nexus instrument (Thermo, USA). Each spectrum was obtained by taking 64 scans with a resolution of 2 cm ^-1 .

Protocols of differential scanning calorimetry (DSC) were obtained using a DSC Pyris 1 instrument from Perkin Elmer. The sample mass in a standard AI crucible was between 3-4 mg and the rate

- 3 031198 heating was 5 ° C / min. The temperature program that was used consisted of 1 min of stabilization at 50 ° C, and then heating to 220 ° C at a heating rate of 5 ° C / min. 4.0 N _{2 was} used as carrier gas at a flow rate of 20 ml / min.

Preparation of tapentadol maleate of formula I, Form A

Example 1

The base of tapentadol (5.2 g; 23.5 mmol) is dissolved in 20.8 ml of tert-butyl methyl ether and the solution is heated to boiling. A solution of maleic acid (2.73 g; 23.5 mmol) in 18 ml of isopropyl alcohol is added dropwise to the solution while boiling. The resulting solution is cooled to a temperature of 40 ° C and a seed of Form A of tapentadol maleate (0.052 g) is added. Then the mixture is cooled to a temperature of 35 ° C and stirred for 1 hour. The resulting suspension is cooled to a temperature of -10 ° C. The separated substance is sucked off and washed with a minimum amount of a mixture of tert-butyl methyl ether / isopropanol (3/1). The final product is then dried in a vacuum dryer at 40 ° C. 6.9 g (87 wt.% Of the theoretical amount) of tapentadol maleate of crystalline Form A, corresponding to the XRPD diffractogram shown in FIG. 1 and the DSC thermogram shown in FIG. 2

Example 2

Tapentadol hydrochloride (6 kg, 23.3 mol) is suspended in 43 l of tert-butyl methyl ether. An aqueous solution of NaOH (980 g in 10 l) is added to the suspension and the reaction mixture is vigorously stirred for 30 minutes. The aqueous phase is separated and the organic phase is washed with 10 l of water. 14 liters of distillate are removed from the reaction mixture by distillation. Distillation is then continued with the continuous addition of dry tert-butyl methyl ether (26 L) at such a rate as to maintain a constant volume in the reaction mixture. 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 l of isopropanol is added. The reaction mixture is cooled to a temperature of 40 ° C and a seed of Form A of tapentadol maleate (60 g) is added. Then the mixture is cooled to a temperature of 35 ° C and stirred for 1 hour. The resulting suspension is cooled to -10 ° C. The separated material is filtered off with suction and washed with 6.5 L of tert-butyl methyl ether / isopropanol (3/1). The final product is then dried in a vacuum dryer at 40 ° C. 7.0 g (90 wt.% Of the theoretical amount) of tapentadol maleate of crystalline Form A, corresponding to the XRPD diffractogram shown in FIG. 1 and the DSC thermogram shown in FIG. 2

Example 3

Tapentadol hydrobromide (300 kg; 1 mol) is suspended in 1.8 L of tert-butyl methyl ether. An aqueous solution of NaOH (42 g in 450 l) is added to the suspension and the reaction mixture is vigorously stirred for 30 minutes. The aqueous phase is separated and the organic phase is washed with 2 x 450 ml of water. 600 ml of distillate are removed from the reaction mixture by distillation. Distillation is then continued with the continuous addition of dry tert-butyl methyl ether (1000 ml) at such a rate as to maintain a constant volume in the reaction mixture. The temperature of the solution is brought 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 to a temperature of 40 ° C and a seed of Form A of tapentadol maleate is added. Then the mixture is cooled to a temperature of 35 ° C and stirred for 1 hour. The resulting suspension is cooled to a temperature of 10 ° C. The separated substance is sucked off and washed with a minimum amount of a mixture of tert-butyl methyl ether / isopropanol (3/1). The final product is then dried in a vacuum dryer at 40 ° C. 305 g (91 wt.% Of the theoretical amount) of tapentadol maleate of crystalline Form A, corresponding to the XRPD diffractogram shown in FIG. 1 and the DSC thermogram shown in FIG. 2

Claims

CLAIM

1. Tapentadol maleate of formula I, Form A, characterized in that it has the following characteristic peaks at a 2-theta reflection angle on a powder X-ray diffractogram, measured using CuKa radiation: 10.7; 11.6; 16.0; 17.1; 20.4; 24.2 and 25.9 ± 0.2 °

2. Tapentadol maleate of formula I, Form A according to claim 1, characterized in that it has a basic temperature for the onset of decomposition of 90.0 ° C, measured using differential scanning calorimetry (DSC).

3. Tapentadol maleate of formula I, Form A according to claim 1 or 2, characterized in that it has the following characteristic absorption peaks: 3217, 2971, 2874, 1705, 1619, 1587, 1534, 1484,

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1351, 1250, 1188 and 1075 cm ^-1 in the IR spectrum.

4. The use of tapentadol maleate of formula I, Form A according to any one of claims 1 to 3 for the preparation of a pharmaceutical composition.

5. The method of obtaining tapentadol maleate of formula I, form A according to any one of claims 1 to 3, comprising the following stages:

a) obtaining a solution of tapentadol base in ether solvents by dissolving the base of tapentadol in ether solvents or by neutralizing the salt of tapentadol in ether solvents by adding a solution of an inorganic base;

b) heating the resulting solution and adding dropwise a solution of maleic acid dissolved in alcohol;

c) adding a crystallization seed of Form A of tapentadol maleate of formula I, cooling the resulting solution, growing the crystals, cooling to the isolation temperature and isolation.

6. A method of producing tapentadol maleate of formula I, Form A according to claim 5, wherein THF (tetrahydrofuran), 2-methyltetrahydrofuran (2-Me-THF), cyclopentylmethyl ether or tert-butylmethyl ether ( MTBE).

7. The method according to claim 5 or 6, where tert-butyl methyl ether (MTBE) is used as the ether solvent in step a).

8. A method according to any one of claims 5-7, wherein tert-butyl methyl ether (MTBE) is used as the ether solvent in step a); tapentadol hydrobromide, oxalate, salicylate or hydrochloride is used as a salt suitable for neutralization; LiOH, NaOH, KOH, K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ or KHCO _{3 is} used as a suitable inorganic base; and where in step a) the resulting solution is dried by removing the azeotropic MTBE / water mixture by azeotropic distillation or using suitable reagents selected from Na ₂ SO ₄ , MgSO ₄ , CaCl ₂ or CaSO ₄ , or using molecular sieves.

9. The method of claim 8, where the tert-butyl methyl ether (MTBE) is used as the ether solvent in step a); tapentadol hydrochloride is used as a salt of tapentadol; NaOH is used as a suitable inorganic base and the drying involves distilling the azeotropic mixture MTBE / water.

10. The method according to any of claims 5-9, where in step a) a solution is obtained containing from 2 to 9 mmol, from 0.5 to 2 g of the base of tapentadol in 4 ml of ether solvent, with a total water content of less than 0.5 wt.%

11. A method according to any of claims 5-10, where in step a) a solution is obtained from 0.5 to 1.2 g of the base of tapentadol dissolved in 4 ml of MTBE, with a total water content of less than 0.5 wt.%.

12. The method according to any of claims 5-11, where the solution obtained in stage a), containing from 0.5 to 1.2 g of the base of tapentadol in 4 ml of MTBE, with a total water content of less than 0.5 wt.%, in stage b) is heated to a temperature above 50 ° C and to this solution is added a solution of maleic acid in alcohol.

13. A method according to any of claims 5 to 12, wherein in step b) maleic acid, dissolved in alcohol, is added in a ratio of from 1 to 1.5 eq. in relation to the base of tapentadol and the rate of addition is chosen so that the internal temperature of the tapentadol solution does not fall below 40 ° C.

14. The method according to any of claims 5 to 13, where in step b) a solution of 0.53 g of maleic acid in 2.5 to 3.5 ml of isopropyl alcohol is added to the solution obtained in step a) containing from 0, 9 to 1.1 g of tapentadol base in 4 ml of MTBE, while the internal temperature is maintained in the range from 50 to 55 ° C.

15. The method according to any of claims 5 to 14, where in step c) the solution obtained in step b) is seeded by adding from 0.5 to 2% of form A of tapentadol maleate at an internal temperature of from 35 to 45 ° C, seeded the reaction mixture is then cooled to an internal temperature of from 30 to 40 ° C and cooling is continued for at least 0.5 h.

16. The method according to any of claims 5-15, where in step c) the solution obtained in step b) is seeded by adding 1% form A of tapentadol maleate, the seeded reaction mixture is then cooled to an internal temperature of 34 to 36 ° C and cooling is continued for at least 0.5 h.

17. The method according to any of paragraphs.5-16, where in stage c) the suspension with crystalline product, obtained after seeding and cooling to an internal temperature of 34 to 36 ° C for at least 0.5 h, is cooled to the separation temperature from 0 to -20 ° C.

18. The method according to any of claims 5-17, where in step c) the suspension with crystalline product, obtained after seeding and cooling to an internal temperature of 34 to 36 ° C for at least 0.5 h, is cooled to the separation temperature from -9 to -11 ° C and the product is filtered off, washed and dried.

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S

but.

N o h X i о h о о and о ς й

V n

42.32

24.96

50.79 55 onset = 90.011 ° C peak = 91.461 ° C area = 312.147 mJ Delta H = 88.678 J / g

100 105 108

Temperature (° C)

FIG. 2