EP3102560A1

EP3102560A1 - A solid form of tapentadol maleate and a method of its preparation

Info

Publication number: EP3102560A1
Application number: EP15710419.1A
Authority: EP
Inventors: Josef Cerny; Ondrej Dammer; Tomas Pekarek; Pavel CALTA
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2014-02-04
Filing date: 2015-01-30
Publication date: 2016-12-14
Also published as: WO2015117576A1; CZ201479A3; EA201691559A1; CZ307492B6; EA031198B1

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 CuKa 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 cm^-1 in the IR spectrum.

Description

A solid form of tapentadol maleate and a method of its preparation

Technical Field

The invention relates to a new crystalline form of tapentadol maleate (I), chemically

3-[(li-,2/?)-3-(dimethylamino)-l -ethyl-2-methylpropyl]phenol maleate and a method of its preparation.

Background Information

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 μ-opioid receptors, it prevents transmission of nerve impulses along the spinal cord and at the same time inhibits reuptake of noradrenaline in synaptic clefts.

Various preparation processes of tapentadol, its optical isomers and pharmaceutically acceptable salts are described in a number of patents or patent applications, e.g. US 6,248,737 and US 6,344,558, further in WO2004108658, WO2005000788, WO2008012046, WO2008012047, WO2008012283, WO2011080736, WO2011157390,

WO20111026314, WO2013105109, WO2012089177, but also in a number of others.

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.). However, out of the entire range of proposed salts it was only the crystalline hydrochloride that was prepared, isolated and sufficiently described. The polymorph of tapentadol hydrochloride isolated this way was identified as Form B. The document WO2006000441 describes two crystalline forms of the hydrochloride: the above mentioned Form B and Form A. Each of the polymorphs 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. Two other polymorphic forms of the free base of tapentadol are also described in the application WO2012001571. A wide range of salts and co-crystals is described in the application O2012010316; however, most of the forms were not physically characterized in any way and no particular process of their preparation was mentioned. A specific form of tapentadol hydrobromide was also described in WO2012051246.

The document US20110071120 describes the preparation and characterization of a few tapentadol salts (camphor sulfonate, dibenzoyl tartrate, malate and salicylate). However, salts with high molecular weight acids (e.g. camphor sulfonic, dibenzoyl tartaric acids 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 as commercially available dosage forms contain 50 to 250 mg of tapentadol (as the hydrochloride). This document also mentions tapentadol maleate, only characterized with XRPD, which was only prepared in a very low yield.

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.

Disclosure of Invention

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

b) heating up the obtained solution and dropwise addition of a solution of maleic acid dissolved in an alcohol

c) 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. 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, K₂C0₃, Na₂C0₃, NaHC0₃, and KHCO₃; 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 Na₂S0 , MgS0 ,CaCl₂, 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.

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. In the most preferred embodiment 0.53 g of maleic acid in 2.5 to 3.5 ml of isopropyl alcohol is added to 0.9 to 1.1 g of tapentadol base dissolved in 4 ml of MTBE, the temperature being mamtained in the range of 50 to 55°C.

The solution obtained this way is, in step c), inoculated by addition of 0.5 to 2% by weight of tapentadol maleate Form A at 40 ± 5°C. In a preferred embodiment 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).

What follows then is cooling to the isolation temperature in the range of 0 to -20°C, preferably to a temperature of -10 ± 1°C, and product isolation. The product is washed with an ether- alcohol mixture, preferably MTBE-isopropyl alcohol, and is dried. The term temperature mentioned in the examples, claims and description always refers to the internal temperature of the mixture, solution or suspension.

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.

Table 1: XRPD - characteristic diffraction peaks of tapentadol maleate Form A of formula I

Pos. [°2Th.l d-spacing [A] Rel. Int. [%]

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 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

Fig. 3: IR spectrum of Form A of tapentadol maleate of formula I

Examples

The samples in the examples below were characterized using the X-ray Powder Diffraction (XRPD), IR Spectroscopy and Differential Scanning Calorimetry (DSC) methods.

Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used Cu a (λ= 0.1547 nm (1.542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ. For the measurement a flat powder sample was used that was placed on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad SoUer slits and a ¼ anti-diffusion slit were used. 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 N₂ was used at the flow rate of 20 ml/min.

Preparation of tapentadol maleate of formula I, Form A Example 1:

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. The separated substance is aspirated and washed with a minimal amount of a mixture of teri-butyl methyl ether/isopropanol (3/1). The final product is then dried in a vacuum drier at 40°C. 6.9 g (87% 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. Example 2:

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. Then, 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.

Example 3:

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. Then, 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.

Claims

Claims:

1. Tapentadol maleate of formula I, Form A, characterized in that it exhibits the following characteristic reflections in an X-ray powder pattern, measured with the use of CuKa radiation: 10.7; 11.6; 16.0; 17.1; 20.4; 24.2 and 25.9 ± 0.2° 2-theta.

2. Tapentadol maleate of formula I, Form A, according to claim 1, characterized in that it exhibits the main onset temperature of 90.0°C when measured using the Differential Scanning Calorimetry (DSC).

3. Tapentadol maleate of formula I, Form A, according to claims 1 and 2, characterized in that it exhibits the following characteristic absorption peaks: 3217, 2971, 2874, 1705, 1619, 1587, 534, 1484, 1351, 1250, 1188 and 1075 cm^"1 in the IR spectrum.

4. Use of tapentadol maleate of formula I, Form A, according to claims 1-3 for the preparation of a pharmaceutical composition.

5. A method for preparing tapentadol maleate of formula I, Form A, according to claims 1- 3, comprising 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;

b) heating up the obtained solution and dropwise addition of a solution of maleic acid dissolved in an alcohol;

c) adding crystallization inocula of Form A of tapentadol maleate of formula I, cooling the obtained solution, crystal growth, cooling to the isolation temperature and isolation.

6. The method for preparing tapentadol maleate of formula I, Form A, according to claim 5, wherein THF, 2-methyl tetrahydrofuran (2-Me-THF), cyclopentyl methyl ether or tert- butyl methyl ether (MTBE) is used as the ethereal solvent in step a).

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

8. The method according to claims 5 to 7, wherein tert-butyl methyl ether (MTBE) is used as the ethereal solvent in step a); tapentadol hydrobromide, oxalate, salicylate of hydrochloride is used as the salt suitable for neutralization; LiOH, NaOH, OH, 2CO3, Na₂C0₃, NaHC0₃, or KHCO3 is used as the suitable inorganic base; and suitable drying is carried out with the use of Na₂S0_4j MgS0_4j CaCl₂, or CaS0₄, with molecular sieves, or by removing the MTBE/water azeotropic mixture by azeotropic distillation.

9. The method according to claims 5 to 8, wherein tert-butyl methyl ether (MTBE) is used as the ethereal solvent in step a); hydrochloride is used as the suitable salt; NaOH is used as the suitable inorganic base; and drying involves distilling off an azeotropic mixture of MTBE/water.

10. The method according to claims 5 to 9, wherein a solution containing 2 to 9 mmol, 0.5 to 2 g of tapentadol base in 4 ml of the ethereal solvent with the total water content below 0.5% by weight is obtained in step a).

11. The method according to claims 5 to 10, wherein a solution of 0.5 to 1.2 g of tapentadol based dissolved in 4 ml of MTBE with the total water content below 0.5% by weight is obtained in step a).

12. The method according to claims 5 to 11, wherein the solution obtained in step a), containing 0.5 to 1.2 g of tapentadol base in 4 ml of MTBE with the total water content of below 0.5% by weight, is, in step b), heated up to a temperature higher than 50°C and a solution of maleic acid in an alcohol starts to be added to this solution.

13. The method according to claims 5 to 1 , wherein, in step b), maleic acid dissolved in an alcohol is added in the ratio of 1 to 1.5 equivalents relative to the tapentadol base and the adding rate is selected such that the internal temperature of the tapentadol solution does not drop below 40°C.

14. The method according to claims 5 to 13, wherein, 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 0.9 to 1.1 g of tapentadol base in 4 ml of MTBE, the internal temperature being maintained in the range of 50 to 55°C.

15. The method according to claims 5 to 14, wherein, in step c), the solution obtained in step b) is inoculated by the addition of 0.5 to 2 % of tapentadol maleate Form A at an internal temperature of 35 to 45 °C, the inoculated reaction mixture is subsequently cooled down to an internal temperature of 30 to 40 °C and the cooling is continued for at least 0.5 hours.

16. The method according to claims 5 to 15, wherein, in step c), the solution obtained in step b) is inoculated by the addition of 1% of tapentadol maleate Form A, the inoculated reaction mixture is subsequently cooled down to an internal temperature of 34 to 36°C and the cooling is continued for at least 0.5 hours.

17. The method according to claims 5 to 16, wherein, in step c), a suspension with the crystalline product is obtained after inoculation and cooling to the internal temperature of 34 to 36°C for at least 0.5 hours, which suspension is cooled down to an isolation temperature of 0 to -20°C.

18. The method according to claims 5 to 18, wherein, in step c), a suspension with the crystalline product is obtained after inoculation and cooling to the internal temperature of 34 to 36°C for at least 0.5 hours, which suspension is cooled down to an isolation temperature from -9 to -11°C, and the product is isolated by filtration, washed and dried.