WO2016058564A1 - Salts of bedaquiline - Google Patents

Salts of bedaquiline Download PDF

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Publication number
WO2016058564A1
WO2016058564A1 PCT/CZ2015/000116 CZ2015000116W WO2016058564A1 WO 2016058564 A1 WO2016058564 A1 WO 2016058564A1 CZ 2015000116 W CZ2015000116 W CZ 2015000116W WO 2016058564 A1 WO2016058564 A1 WO 2016058564A1
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Prior art keywords
bedaquiline
salt
exhibits
acid
sulphate
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PCT/CZ2015/000116
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French (fr)
Inventor
Pavel ZVATORA
Ondrej Dammer
Ludek Ridvan
Petr Lustig
Tomas Pekarek
Martin STEFKO
Lukas KREJCIK
Marcela Tkadlecova
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Zentiva, K.S.
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Publication of WO2016058564A1 publication Critical patent/WO2016058564A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the invention relates to new solid forms of (lii s 2)S)-l-(6-Bromo-2-methoxy-3-quinolyl)-4- dimemylamino-2-(l-naphthyl)-l-p enyl-butan-2-ol of formula I,
  • bedaquiline ( 1 R, 2S)- 1 - (6-Bromo-2-methoxy-3 -qumolyl)-4-dimemylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol, which is known as bedaquiline (CAS no. 843663-66-1) and belongs to the group of quinoline derivatives that can be used as microbial inhibitors.
  • the salt bedaquiline fumarate (1:1) is suitable for treatment or prevention of resistant microbial infections, especially microbial tuberculosis infections.
  • Bedaquiline fumarate exists in one non-solvated crystalline form (Form A) and two pseudo- polymorphic forms B and C. Solubility of this salt in water is very low, even if aqueous solutions with varying pH are used. It is clear that more solid forms of bedaquiline are necessary for the preparation of a dosage form with higher solubility and bioavailability.
  • the invention provides a process for preparing solid forms of bedaquiline salts, wherein (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-l -naphthalenyl-beta- phenyl-3-quinoline-ethanol is mixed with an inorganic acid selected from sulphuric or phosphoric acid, or an organic acid selected from tartaric or citric acid, in a suitable solvent.
  • the prepared new solid forms have suitable physico-chemical characteristics for use in the pharmaceutical industry and formulation of new dosage forms.
  • This invention provides several solid-phase salts of bedaquiline either in a crystalline or amorphous form, or as a mixture of amorphous and crystalline forms.
  • bedaquiline sulphate is preferred, which can be prepared both in crystalline and amorphous solid phases.
  • the invention provides a new solid form of bedaquiline with sulphuric acid, phosphoric acid, tartaric acid or citric acid.
  • the new solid forms of bedaquiline with these acids can be prepared in a crystalline form, amorphous form, or in a mixture of amorphous and crystalline forms in adequate yields with high chemical purity.
  • the prepared new solid forms of bedaquiline may have various internal arrangements (polymorphism) with different physico-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratios.
  • the new solid forms of bedaquiline are prepared by a reaction of bedaquiline base with sulphuric acid, phosphoric acid, tartaric acid or citric acid.
  • the reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water, or mixtures thereof.
  • a suitable solvent which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water, or mixtures thereof.
  • Aliphatic C C 4 alcohols, esters or their mixtures are preferred.
  • the most commonly used solvents include isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
  • the resulting product is precipitated or crystallized, typically at temperatures in the range of from -30°C to the boiling point of the solvent.
  • the free base of bedaquiline was prepared in accordance with the method described in the patent application (WO 2006125769) and was characterized by X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), IR Spectroscopy, and NMR Spectroscopy, wherein these data have not been published in the literature yet.
  • the crystalline form of the free base of bedaquiline is characterized by the reflections presented in Table 1.
  • Table 1 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 8.1; 11.4; 16.1; 18.4; 22.3; 24.4 and 26.8 ⁇ 0.2° 2-theta.
  • An example of the X-ray powder pattern is shown in Figure 1.
  • Table 1 An example of the X-ray powder pattern is shown in Figure 1.
  • the melting point of the free base of bedaquiline is 181°C (DSC).
  • the crystalline form of bedaquiline fumarate is characterized by the reflections presented in Table 2.
  • Table 2 includes reflections whose relative intensity value is higher than 1 percent.
  • the characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 5.9; 10.3; 14.0; 16.8; 20.4 and 23.0° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 2.
  • the DSC record of bedaquiline fumarate shows a major endotherm with the peak at 205X (DSC).
  • the new solid forms in accordance with this invention can be both anhydrous or non-solvated and in the form of hydrates solvates of the respective solvents. They can be crystalline, amorphous, or they can contain the crystalline and amorphous phases in different ratios.
  • the characteristic reflections of the crystalline form of bedaquiline sulphate are shown in Table 3.
  • Table 3 includes reflections whose relative intensity value is higher than 1 percent
  • the characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 7.7; 12.4; 15.8; 19.2; 20.2; 22.3 and 25.1° ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 6.
  • the crystalline form of bedaquiline sulphate may contain solvents (incl. water) in different molar ratios.
  • Figure 8 shows an example of the 1H NMR spectrum of the prepared bedaquiline sulphate.
  • the DSC curve of bedaquiline sulphate is shown in Figure 9. According to this example the melting point of bedaquiline sulphate is 188°C.
  • bedaquiline sulphate The infrared spectrum of bedaquiline sulphate is shown in Figure 10.
  • the molar ratio of bedaquiline ; sulphuric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
  • the X-ray powder pattern of the new solid form of bedaquiline tartrate is shown in Figure 11. This salt may contain an amorphous fraction.
  • Figure 12 shows an example of the 1H NMR spectrum of the prepared bedaquiline tartrate.
  • the molar ratio of bedaquiline : tartaric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
  • the DSC curve of bedaquiline tartrate is shown in Figure 13. According to this example the melting point of bedaquiline tartrate is 103°C.
  • Figure 16 shows an example of the ⁇ NMR spectrum of the prepared bedaquiline citrate.
  • the molar ratio of bedaquiline : citric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
  • the DSC curve of bedaquiline citrate is shown in Figure 17. According to this example the melting point of bedaquiline citrate is 102°C.
  • Table 4 The characteristic reflections of the crystalline form of bedaquiline citrate are shown in Table 4.
  • Table 4 includes reflections whose relative intensity value is higher than 1 percent.
  • An example of the X-ray powder pattern is shown in Figure 19. This salt may contain an amorphous fraction.
  • Figure 20 shows an example of the 1H NMR spectrum of the prepared bedaquiline phosphate.
  • the DSC curve of bedaquiline phosphate is shown in Figure 21.
  • the melting point of bedaquiline phosphate is 159°C.
  • bedaquiline phosphate The infrared spectrum of bedaquiline phosphate is shown in Figure 22.
  • the molar ratio of bedaquiline : phosphoric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
  • a 10mm mask and a 1/4° fixed anti-dispersion slit were used.
  • the irradiated area of the sample is 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used. Infrared spectroscopy
  • ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS Br detector, in the measurement range of 600 to 4000 cm “1 and the spectral resolution of 4.0 cm “1 .
  • the data were obtained at 64 spectrum accumulations.
  • the OMNIC 6.2 software was used to process the spectra.
  • the records of bedaquiline base and the fumarate were measured with the DSC Pyris 1 device made by Perkin Elmer.
  • the sample charge in a standard Al pot was between 3 mg and the heating rate was 10 °C/min.
  • the temperature program that was used consists of 1 min of stabilization at the temperature of 20 °C and then of heating up to 250 °C at the heating rate of 10°C/min. 4.0 N 2 at the flow rate of 20 ml/rnin was used as the carrier gas.
  • Bedaquiline fumarate was prepared according to the procedure described in the patent EP 2086940, Example A. Yield 138.5 mg (45 %). Melting point 205 °C (DSC). HPLC purity 99.6 %. XRPD: Fig. 2.

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Abstract

The invention relates to new solid forms of (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4- dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol of formula I, known as bedaquiline, and processes for preparing the same. The process for preparing solid forms of bedaquiline salts consists in mixing of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy- alpha-1-naphthalenyl-beta-phenyl-3-quinoline-ethanol with an inorganic acid selected from sulphuric or phosphoric acid, or an organic acid selected from tartaric or citric acid, in a suitable solvent.

Description

Salts of Bedaquiline
Technical Field The invention relates to new solid forms of (liis2)S)-l-(6-Bromo-2-methoxy-3-quinolyl)-4- dimemylamino-2-(l-naphthyl)-l-p enyl-butan-2-ol of formula I,
Figure imgf000003_0001
Background Art
( 1 R, 2S)- 1 - (6-Bromo-2-methoxy-3 -qumolyl)-4-dimemylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol, which is known as bedaquiline (CAS no. 843663-66-1) and belongs to the group of quinoline derivatives that can be used as microbial inhibitors. The salt bedaquiline fumarate (1:1) is suitable for treatment or prevention of resistant microbial infections, especially microbial tuberculosis infections.
Preparation of this molecule and its use for the treatment of microbial diseases is described in the patent application (WO 2004/011436). Preparation of the salt of bedaquiline with fumaric acid (1:1) (bedaquiline fumarate) and its pharmaceutical compositions are described in the patent (EP 2 086 940). This salt may be prepared by a reaction of the corresponding free base with fumaric acid in the ratio of (1 :1) in a suitable solvent, such as isopropyl alcohol. The resulting salt is obtained from the suspension by filtration as a white solid substance.
Bedaquiline fumarate exists in one non-solvated crystalline form (Form A) and two pseudo- polymorphic forms B and C. Solubility of this salt in water is very low, even if aqueous solutions with varying pH are used. It is clear that more solid forms of bedaquiline are necessary for the preparation of a dosage form with higher solubility and bioavailability.
Disclosure of Invention
The invention provides a process for preparing solid forms of bedaquiline salts, wherein (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-l -naphthalenyl-beta- phenyl-3-quinoline-ethanol is mixed with an inorganic acid selected from sulphuric or phosphoric acid, or an organic acid selected from tartaric or citric acid, in a suitable solvent. The prepared new solid forms have suitable physico-chemical characteristics for use in the pharmaceutical industry and formulation of new dosage forms.
Brief Description of Drawings Figure 1. X-ray powder pattern of the free base of bedaquiline
Figure 2. X-ray powder pattern of bedaquiline fumarate
Figure 3. 1HNMR of bedaquiline fumarate
Figure 4. DSC curve of bedaquiline fumarate
Figure 5. IR spectrum of bedaquiline fumarate
Figure 6. X-ray powder pattern of bedaquiline sulphate - crystalline form
Figure 7. X-ray powder pattern of bedaquiline sulphate - amorphous form
Figure 8. 1H NMR of bedaquiline sulphate
Figure 9. DSC curve of bedaquiline sulphate
Figure 10. IR spectrum of bedaquiline sulphate
Figure 11. X-ray powder pattern of bedaquiline tartrate
Figure 12. 1H NMR of bedaquiline tartrate
Figure 13. DSC curve of bedaquiline tartrate
Figure 14. IR spectrum of bedaquiline tartrate
Figure 15. X-ray powder pattern of bedaquiline citrate
Figure 16. 1H NMR of bedaquiline citrate
Figure 17. DSC curve of bedaquiline citrate
Figure 18. IR spectrum of bedaquiline citrate
Figure 19. X-ray powder pattern of bedaquiline phosphate Figure 20. 1H NMR of bedaquiline phosphate
Figure 21. DSC curve of bedaquiline phosphate
Figure 22. IR spectrum of bedaquiline phosphate Detailed description of the invention
Although preparation of a salt by a reaction of an acid and a base is a well-known method, it is always a problem to obtain the desired salts in the solid phase and in a purity corresponding to the requirements for their pharmaceutical use. Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more quickly soluble, it cannot often be obtained in the required quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable, its desired purity is easier to achieve and it dissolves more slowly. Mixtures of the amorphous and crystalline solid phases may represent a solution to the problem.
This invention provides several solid-phase salts of bedaquiline either in a crystalline or amorphous form, or as a mixture of amorphous and crystalline forms. In the invention, bedaquiline sulphate is preferred, which can be prepared both in crystalline and amorphous solid phases.
The invention provides a new solid form of bedaquiline with sulphuric acid, phosphoric acid, tartaric acid or citric acid.
The new solid forms of bedaquiline with these acids can be prepared in a crystalline form, amorphous form, or in a mixture of amorphous and crystalline forms in adequate yields with high chemical purity.
These new solid forms can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
The prepared new solid forms of bedaquiline may have various internal arrangements (polymorphism) with different physico-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratios.
These new solid forms are suitable for preparation of bedaquiline with a high chemical and optical purity.
The new solid forms of bedaquiline (formula I) are prepared by a reaction of bedaquiline base with sulphuric acid, phosphoric acid, tartaric acid or citric acid. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water, or mixtures thereof. Aliphatic C C4 alcohols, esters or their mixtures are preferred. The most commonly used solvents include isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
The resulting product is precipitated or crystallized, typically at temperatures in the range of from -30°C to the boiling point of the solvent.
The free base of bedaquiline was prepared in accordance with the method described in the patent application (WO 2006125769) and was characterized by X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), IR Spectroscopy, and NMR Spectroscopy, wherein these data have not been published in the literature yet. The crystalline form of the free base of bedaquiline is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 8.1; 11.4; 16.1; 18.4; 22.3; 24.4 and 26.8 ± 0.2° 2-theta. An example of the X-ray powder pattern is shown in Figure 1. Table 1
Interplanar
Position spacing Rel. Intensity
(°2 Theta) if (A)=0.1 nm (%)
4.99 17.705 13.4
7.01 12.609 8.2
8.19 10.789 85.4
9.85 8.970 11.6
10.60 8.341 32.0
10.87 8.131 44.4
11.41 7.750 100.0
11.79 7.501 46.2
12.65 6.991 10.9
13.23 6.686 39.7
13.92 6.359 24.9
14.93 5.929 9.9
15.43 5.736 16.8
16.07 5.510 48.3 16.92 5.236 9.1
17.37 5.101 19.9
17.94 4.942 53.2
18.35 4.830 56.5
18.70 4.742 41.7
19.62 4.521 26.6
20.05 4.425 40.7
20.68 4.292 26.9
21.15 4.197 40.9
21.71 4.091 12.9
22.29 3.986 51.5
22.78 3.901 14.3
23.23 3.826 35.3
23.49 3.784 9.7
24.39 3.647 52.3
24.91 3.572 12.5
25.29 3.519 10.8
25.69 3.465 21.0
26.13 3.408 9.5
26.86 3.316 34.3
27.30 3.264 17.9
28.20 3.162 11.8
28.88 3.089 18.2
30.00 2.976 13.4
31.01 2.881 7.2
32.38 2.763 6.6
34.36 2.608 7.7
36.87 2.436 4.7
In this case, the melting point of the free base of bedaquiline is 181°C (DSC).
The crystalline form of bedaquiline fumarate, the preparation of which was described in the patent (EP 2086940), is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 5.9; 10.3; 14.0; 16.8; 20.4 and 23.0° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 2.
Table 2
Interplanar
Position spacing Rel. Intensity
(°2 Theta) d (A)=0.1 nm (%)
5.92 14.928 60.1
10.26 8.618 27.9
11.84 7.470 24.4
11.96 7.391 27.5
12.45 7.102 6.8
13.11 6.748 21.3
14.01 6.315 40.0
14.62 6.055 11.1
16.78 5.279 20.2
18.02 4.918 11.1
18.79 4.720 14.0
19.20 4.618 9.3
19.90 4.459 15.5
20.38 4.355 28.8
20.72 4.284 13.4
21.40 4.148 29.5
23.04 3.858 100.0
23.77 3.740 6.3
24.16 3.681 4.5
24.75 3.594 10.8
25.57 3.481 10.7
26.72 3.334 6.3
27.14 3.283 8.3
27.87 3.198 4.2
28.51 3.129 6.5
29.60 3.016 5.2 34.28 2.614 16.3
1H NMR spectrum of bedaquiline fumarate is shown in Fig. 3. The resulting stoichiometric ratio corresponds to the ratio of (1:1).
The DSC record of bedaquiline fumarate (Figure 4) shows a major endotherm with the peak at 205X (DSC).
The infrared spectrum of bedaquiline fumarate is shown in Fig. 5.
The new solid forms in accordance with this invention can be both anhydrous or non-solvated and in the form of hydrates solvates of the respective solvents. They can be crystalline, amorphous, or they can contain the crystalline and amorphous phases in different ratios.
The characteristic reflections of the crystalline form of bedaquiline sulphate are shown in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1 percent The characteristic diffraction peaks of the free base of bedaquiline in accordance with this invention are: 7.7; 12.4; 15.8; 19.2; 20.2; 22.3 and 25.1° ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 6.
Table 3
Interplanar Rel.
Position spacing Intensity
(°2 Theta) d (A) (%)
4.40 20.049 9.1
5.80 15.222 17.6
7.72 11.449 32.9
10.20 8.669 13.4
11.76 7.520 35.9
12.40 7.133 95.8
13.46 6.573 23.4
13.77 6.426 41.0
15.77 5.615 53.7
16.15 5.485 28.5
16.62 5.329 29.2
16.99 5.213 14.8 17.55 5.049 14.9
17.98 4.928 11.8
18.30 4.844 21.8
19.24 4.610 100.0
20.24 4.383 64.4
20.81 4.266 21.9
21.11 4.204 17.9
21.53 4.124 37.3
22.28 3.986 42.9
22.63 3.927 22.1
22.96 3.871 16.5
23.47 3.787 18.4
23.95 3.713 26.0
24.63 3.612 18.5
25.08 3.548 42.9
26.16 3.404 27.7
26.58 3.351 34.5
27.02 3.298 11.1
28.02 3.182 14.0
29.27 3.049 8.0
29.88 2.988 7.2
30.82 2.899 17.4
31.19 2.865 7.3
37.70 2.384 8.3
The crystalline form of bedaquiline sulphate may contain solvents (incl. water) in different molar ratios.
Figure 8 shows an example of the 1H NMR spectrum of the prepared bedaquiline sulphate. The DSC curve of bedaquiline sulphate is shown in Figure 9. According to this example the melting point of bedaquiline sulphate is 188°C.
The infrared spectrum of bedaquiline sulphate is shown in Figure 10. The molar ratio of bedaquiline ; sulphuric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2. The X-ray powder pattern of the new solid form of bedaquiline tartrate is shown in Figure 11. This salt may contain an amorphous fraction.
Figure 12 shows an example of the 1H NMR spectrum of the prepared bedaquiline tartrate. The molar ratio of bedaquiline : tartaric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
The DSC curve of bedaquiline tartrate is shown in Figure 13. According to this example the melting point of bedaquiline tartrate is 103°C.
The infrared spectrum of bedaquiline tartrate is shown in Figure 14.
The X-ray powder pattern of the new solid form of bedaquiline citrate is shown in Figure 15. This salt may contain an amorphous fraction.
Figure 16 shows an example of the Ή NMR spectrum of the prepared bedaquiline citrate. The molar ratio of bedaquiline : citric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
The DSC curve of bedaquiline citrate is shown in Figure 17. According to this example the melting point of bedaquiline citrate is 102°C.
The irifrared spectrum of bedaquiline citrate is shown in Figure 18.
The characteristic reflections of the crystalline form of bedaquiline citrate are shown in Table 4. Table 4 includes reflections whose relative intensity value is higher than 1 percent. An example of the X-ray powder pattern is shown in Figure 19. This salt may contain an amorphous fraction.
Table 4
Interplanar
Position spacing Rel. Intensity
(°2 Theta) </(A)=0.1 nm (%)
5.99 14.743 9.4
7.10 12.435 12.5
12.27 7.209 91.3
12.73 6.951 79.7
14.15 6.256 32.0
14.53 6.090 31.7 15.94 5.554 8.0
17.76 4.990 14.3
18.38 4.824 10.2
19.17 4.626 6.8
20.10 4.413 21.6
21.97 4.043 53.3
22.71 3.912 100.0
24.12 3.686 50.8
Figure 20 shows an example of the 1H NMR spectrum of the prepared bedaquiline phosphate.
The DSC curve of bedaquiline phosphate is shown in Figure 21. According to this example the melting point of bedaquiline phosphate is 159°C.
The infrared spectrum of bedaquiline phosphate is shown in Figure 22. The molar ratio of bedaquiline : phosphoric acid may be in the range of 10:1 to 1:3, preferably 1:1, 2:1 and 1:2.
Experimental part X-ra powder diffraction
The diffracto grams were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=0.1542 nm (0. 542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used. Infrared spectroscopy
ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS Br detector, in the measurement range of 600 to 4000 cm"1 and the spectral resolution of 4.0 cm"1. The data were obtained at 64 spectrum accumulations. The OMNIC 6.2 software was used to process the spectra.
Differential Scanning Calorimetry (DSC)
The records of bedaquiline base and the fumarate were measured with the DSC Pyris 1 device made by Perkin Elmer. The sample charge in a standard Al pot was between 3 mg and the heating rate was 10 °C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 20 °C and then of heating up to 250 °C at the heating rate of 10°C/min. 4.0 N2 at the flow rate of 20 ml/rnin was used as the carrier gas.
The records of the other new solid forms of bedaquiline were measured with the Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 μί,) was between 4 and 5 mg and the heating rate was 5°C/rnin. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 220°C at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). 5.0 N2 at the flow rate of 50 ml/min was used as the carrier gas. tHNMR
For the structural characterization 1H NMR spectroscopy at 250 MHz by Bruker Avance 250 was used. As the solvent deuterated D6-dimethyl sulfoxide was used and the measurements were carried out at the temperature of 303 K. As the internal reference with 0.00 ppm trimethylsilane (TMS) was used.
Examples
Example ί
Crude bedaquiline was prepared according to the procedure described in the patent application WO 2006/125769, Example C. The resulting product was filtered, washed with ethanol and dried in a vacuum drier for 16 hours. Yield 28 %. Melting point 181 °C (DSC). HPLC purity 99.3 %. XRPD: Fig. 1. Example 2
Bedaquiline fumarate was prepared according to the procedure described in the patent EP 2086940, Example A. Yield 138.5 mg (45 %). Melting point 205 °C (DSC). HPLC purity 99.6 %. XRPD: Fig. 2.
Example 3
Preparation of crystalline bedaquiline sulphate
(1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 14 ml of isopropyl alcohol. 18.4 mg (0.18 mmol) of sulphuric acid (96%) was added to this suspension. The resulting solution was slowly concentrated by partial evaporation of the solvent (about 7 ml) at the room temperature. The separated crystalline product was removed by filtration and dried at 30 to 40°C. Yield 39 mg (33%). Melting point 188 °C (DSC). XRPD: Fig. 6. Example 4
Preparation of amorphous bedaquiline sulphate
( 1 R,2S)~ 1 - (6-Brorno-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 14 ml of isopropyl alcohol. 18.4 mg (0.18 mmol) of sulphuric acid (96%) was added to this suspension. During slow evaporation of the solvent at the room temperature the crystalline product was separated, which was filtered off and dried at 90 to 110°C. Yield 40 mg (34%). XRPD: Fig. 7.
Example 5
Preparation of bedaquiline tartrate
( 1 R,2S)- 1 - (6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 4 ml of acetonitrile. 27 mg (0.18 mmol) of tartaric acid was added to this suspension. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 43 mg (34%). Melting point 103°C (DSC). XRPD: Fig. 10. Example 6
Preparation of bedaquiline citrate
( 1 R ,25)- 1 - (6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 8 ml of isopropyl alcohol. 34.6 mg (0.18 mmol) of citric acid was added to this suspension. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 50 mg (37%). Melting point 102°C (DSC). XRPD: Fig. 14.
Example 7
Preparation of bedaquiline phosphate
(1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -qwnolyl)-4-dimemylamino-2-(l -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was dissolved in 20 ml of tetrahydrofuxan. 20.8 mg (0.18 mmol) of phosphoric acid (85%) was added to this solution. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 40 mg (33%). Melting point 159°C (DSC). XRPD: Fig. 18.

Claims

Claims
1. A process for preparing solid forms of bedaquiline salts, characterized in that (alpha S, beta R)-6-bromo-alpha-[2-(dimemylarnino)ethyl]-2-methoxy-alpha- 1 -naphthalenyl- beta-phenyl-3-quinoline-ethanol is mixed with an inorganic acid selected from sulphuric and phosphoric acid, or with an organic acid selected from tartaric and citric acid, in a suitable solvent.
2. The process according to claim 1, characterized in that the solvent is selected from the roup consisting of isopropyl alcohol, acetonitrile and tetrahydrofuran.
3. The process according to claim 1, characterized in that the molar ratio of bedaquiline and the inorganic or organic acid is in the range of 10 : 1 to 1 : 3, preferably 1: 1, 2 : 1 or 1 : 2.
4. The salt of bedaquiline with sulphuric acid in the solid phase, obtained by the process according to claims 1 to 3.
5. Bedaquiline sulphate according to claim 4 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 7.7; 12.4; 15.8; 19.2;
20.2; 22.3 and 25.1° ± 0.2° 2-theta.
6. Bedaquiline sulphate according to claim 4 in a crystalline form, which exhibits the maximum peak at 188°C in the DSC record.
7. Bedaquiline sulphate according to claim 4 in a crystalline form, which is solvated by isopropyl alcohol.
8. Bedaquiline sulphate according to claim 4 in an amorphous form.
9. The salt of bedaquiline with sulphuric acid in the solid phase.
10. Bedaquiline sulphate according to claim 9 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 7.7; 12.4; 15.8; 19.2; 20.2; 22.3 and 25.1° ± 0.2° 2-theta.
11. Bedaquiline sulphate according to claim 9 in a crystalline form, which exhibits the maximum peak at 188°C in the DSC record.
12. Bedaquiline sulphate according to claim 9 in a crystalline form, which is solvated by isopropyl alcohol.
13. Bedaquiline sulphate according to claim 9 in an amorphous form.
14. The salt of bedaquiline with tartaric acid in the solid phase, obtained by the process according to claims 1 to 3.
15. The salt according to claim 14, which exhibits the maximum peak at 103°C in the DSC record.
16. The salt of bedaquiline with tartartic acid in the solid phase.
17. The salt according to claim 16, which exhibits the maximum peak at 103°C in the DSC record.
18. The salt of bedaquiline with citric acid in the solid phase, obtained by the process according to claims 1 to 3.
19. The salt according to claim 18 in an amorphous form, which exhibits the maximum peak at 102°C in the DSC record.
20. The salt of bedaquiline with citric acid in the solid phase.
21. The salt according to claim 20 in an amorphous form, which exhibits the maximum peak at 102°C in the DSC record.
22. The salt of bedaquiline with phosphoric acid in the solid phase, obtained by the process according to claims 1 to 3.
23. The salt according to claim 22, which exhibits the maximum peak at 159°C in the DSC record.
24. The salt of bedaquiline with phosphoric acid in the solid phase.
25. The salt according to claim 24, which exhibits the maximum peak at 159°C in the DSC record.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198031A1 (en) * 2015-06-09 2016-12-15 Zentiva, K.S. A salt of bedaquiline with citric acid
CN106316943A (en) * 2016-07-27 2017-01-11 重庆华邦制药有限公司 Refining method of bedaquiline fumarate crystal form compound
US10196360B2 (en) * 2015-10-20 2019-02-05 Zhejiang Hisun Pharmaceutical Co., Ltd. Crystal forms of bedaquiline fumarate and preparation methods therefor

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WO2004011436A1 (en) 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Quinoline derivatives and their use as mycobacterial inhibitors
WO2006125769A1 (en) 2005-05-25 2006-11-30 Janssen Pharmaceutica N.V. Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol
WO2008068231A1 (en) * 2006-12-05 2008-06-12 Janssen Pharmaceutica N.V. Fumarate salt of (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011436A1 (en) 2002-07-25 2004-02-05 Janssen Pharmaceutica N.V. Quinoline derivatives and their use as mycobacterial inhibitors
WO2006125769A1 (en) 2005-05-25 2006-11-30 Janssen Pharmaceutica N.V. Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol
WO2008068231A1 (en) * 2006-12-05 2008-06-12 Janssen Pharmaceutica N.V. Fumarate salt of (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol
EP2086940A1 (en) 2006-12-05 2009-08-12 Janssen Pharmaceutica N.V. Fumarate salt of (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198031A1 (en) * 2015-06-09 2016-12-15 Zentiva, K.S. A salt of bedaquiline with citric acid
US10196360B2 (en) * 2015-10-20 2019-02-05 Zhejiang Hisun Pharmaceutical Co., Ltd. Crystal forms of bedaquiline fumarate and preparation methods therefor
CN106316943A (en) * 2016-07-27 2017-01-11 重庆华邦制药有限公司 Refining method of bedaquiline fumarate crystal form compound

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