WO2016198031A1 - A salt of bedaquiline with citric acid - Google Patents
A salt of bedaquiline with citric acid Download PDFInfo
- Publication number
- WO2016198031A1 WO2016198031A1 PCT/CZ2016/000063 CZ2016000063W WO2016198031A1 WO 2016198031 A1 WO2016198031 A1 WO 2016198031A1 CZ 2016000063 W CZ2016000063 W CZ 2016000063W WO 2016198031 A1 WO2016198031 A1 WO 2016198031A1
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- WO
- WIPO (PCT)
- Prior art keywords
- bedaquiline
- citric acid
- salt
- citrate
- alpha
- 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.)
- Ceased
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Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to a novel solid form of (li?,2S)-l-(6-bromo-2-methoxy-3-quinolyl)-4- dimethylamino-2-(l-naphthyl)-l- henyl-butan-2-ol of formula (I),
- bedaquiline ( 1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl- butan-2-ol
- 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.
- the invention provides a solid form of bedaquiline with citric acid and methods of its preparation.
- the crystalline salt is prepared by a reaction of bedaquiline in the free base form with citric acid in a suitable solvent or mixtures of solvents.
- the prepared salt has advantageous physical-chemical characteristics for use in the pharmaceutical industry and in formulation of new dosage forms.
- FIG. 1 X-ray powder pattern of bedaquiline citrate (prepared in accordance with Process 2).
- Figure 2. IR spectrum of bedaquiline citrate (prepared in accordance with Process 2).
- a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly.
- This invention provides a crystalline salt of bedaquiline in the solid phase.
- the invention provides a novel solid form of bedaquiline with citric acid that can be prepared and isolated in a crystalline form in adequate yields with high chemical purity.
- This solid form can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
- the prepared novel solid form of bedaquiline may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its preparation. For this reason, the invention relates to the crystalline form of bedaquiline with citric acid or its mixtures in any ratio.
- This solid form is suitable for preparation and isolation of bedaquiline with high chemical and optical purity.
- the preparation of the solid form of bedaquiline of formula I is carried out by reaction of the free base of bedaquiline with 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 their mixtures.
- Aliphatic Q-C4 alcohols, esters or their mixtures are preferred.
- the most commonly used solvents are isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
- the final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent.
- the crystalline form of bedaquiline citrate (according to Example 2) 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 bedaquiline citrate in accordance with this invention are as follows: 10.3; 12.0; 13.1; 18.3; 19.7 and 22,0 ⁇ 0.2° 2-theta.
- An example of the X-ray powder pattern is shown in Figure 1.
- the melting point of bedaquiline citrate is 174°C (DSC).
- 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.
- ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 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 record of bedaquiline citrate was measured using a Discovery DSC device made by TA Instruments.
- the sample charge in a standard Al pot (40 yiL) was 4-5 mg and the heating rate was 5°C/min.
- As the carrier gas 5.0 N 2 was used at the flow rate of 50 ml/min.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel solid form 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 methods of its preparation.
Description
A salt of bedaquiline with citric acid
Technical Field
The invention relates to a novel solid form of (li?,2S)-l-(6-bromo-2-methoxy-3-quinolyl)-4- dimethylamino-2-(l-naphthyl)-l- henyl-butan-2-ol of formula (I),
known as bedaquiline, and methods of its preparation. Background Art
( 1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl- butan-2-ol 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 (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 2086 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.
Bedaquiline fumarate exists in one non-solvated crystalline form (Form A) and two pseudo- polymorphic forms B and C.
The solubility of the crystalline free base of bedaquiline in water is very low, even if aqueous solutions with different pH are used. It is clear that novel solid forms of this active
pharmaceutical ingredient are necessary for the preparation of a dosage form with higher solubility and bioavailability.
Disclosure of Invention
The invention provides a solid form of bedaquiline with citric acid and methods of its preparation. The crystalline salt is prepared by a reaction of bedaquiline in the free base form with citric acid in a suitable solvent or mixtures of solvents.
The prepared salt has advantageous physical-chemical characteristics for use in the pharmaceutical industry and in formulation of new dosage forms.
Brief Description of Drawings
Figure 1. X-ray powder pattern of bedaquiline citrate (prepared in accordance with Process 2). Figure 2. IR spectrum of bedaquiline citrate (prepared in accordance with Process 2).
Detailed description of the invention
Although preparation of a salt by a reaction of an acid and base is a well-known method, it is always a problem to obtain the required salts in the solid phase and purity corresponding to the demands for their pharmaceutical use. Bioavailability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily soluble, it cannot often be obtained in an adequate quality and it is also often unstable.
Conversely, compared to the amorphous form, a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly.
This invention provides a crystalline salt of bedaquiline in the solid phase.
The invention provides a novel solid form of bedaquiline with citric acid that can be prepared and isolated in a crystalline form in adequate yields with high chemical purity.
This solid form can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
The prepared novel solid form of bedaquiline may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its preparation. For this reason, the invention relates to the crystalline form of bedaquiline with citric acid or its mixtures in any ratio.
This solid form is suitable for preparation and isolation of bedaquiline with high chemical and optical purity.
The preparation of the solid form of bedaquiline of formula I is carried out by reaction of the free base of bedaquiline with 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 their mixtures. Aliphatic Q-C4 alcohols, esters or their mixtures are preferred. The most commonly used solvents are isopropanol, acetonitrile, tetrahydrofuran or their mixtures.
The final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent.
The free base of bedaquiline was prepared in accordance with the procedure mentioned in the patent (WO 2006125769).
The crystalline form of bedaquiline citrate (according to Example 2) 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 bedaquiline citrate in accordance with this invention are as follows: 10.3; 12.0; 13.1; 18.3; 19.7 and 22,0 ± 0.2° 2-theta. An example of the X-ray powder pattern is shown in Figure 1.
Table 1
Interplanar Rel.
Position spacing Intensity
(°2 Theta) d(A) (%)
5.35 16.493 28.3
8.25 10.710 14.8
9.57 9.238 11.6
10.28 8.597 50.0
10.68 8.280 39.1
12.04 7.344 66.3
13.11 6.750 77.7
13.84 6.392 40.0
16.02 5.528 32.3
17.04 5.199 38.5
17.58 5.041 29.6
18.28 4.848 58.9
19.69 4.504 100.0
20.21 4.390 36.7
21.38 4.152 37.2
21.97 4.043 64.5
22.46 3.955 58.4
23.15 3.839 11.8
24.17 3.680 35.4
24.85 3.581 26.2
26.80 3.324 38.5
27.84 3.203 10.2
28.57 3.121 16.3
31.82 2.810 16.2
33.24 2.693 13.9
35.60 2.520 8.8
In this case, the melting point of bedaquiline citrate is 174°C (DSC).
The infrared spectrum of bedaquiline citrate is shown in Figure 2.
Experimental part
X-ray powder diffraction
The diffractograms were obtained using an XTERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 20, increment: 0.01° 20 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 KBr detector, in the measurement range of 600-4000 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 record of bedaquiline citrate was measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 yiL) was 4-5 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 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). As the carrier gas 5.0 N2 was used at the flow rate of 50 ml/min.
Examples
Example 1
Crude bedaquiline was prepared according to the method described in the patent 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%.
Example 2
Preparation of bedaquiline citrate
( 1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl- butan-2-ol in the quantity of 3.995 mg (7.2· 10"4 mol) was suspended in 85 ml of isopropyl alcohol. 1.3685 mg (7. -10"4 mol) of citric acid was added to this suspension. This suspension was heated up to 80°C (slightly turbid solution). Being continuously stirred, this solution was left to slowly cool down to 50°C and left to be stirred at this temperature for 1 hour. Being continuously stirred, the obtained suspension was left to slowly cool down to the room temperature and filtered. The solid fraction was dried in a vacuum drier at the pressure of 20 kPa and temperature of 50°C for 16 hours. Yield 5.180 mg (96.6%). Melting point 174°C (DSC). XRPD: Fig. 1.
Claims
1. A salt of bedaquiline with citric acid in the solid phase.
2. Bedaquiline citrate according to claim 1 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 10.3; 12.0; 13.1; 18.3; 19.7 and 22,0 ± 0.2° 2-theta.
3. Bedaquiline citrate according to claim 1 in a crystalline form, which exhibits a peak with maximum at 174°C in the DSC record.
4. A process for preparing the solid form of bedaquiline citrate as defined in claims 1 to 4, characterized in that (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2- methoxy-alpha-l-naphthalenyl-beta-phenyl-3-quinoline ethanol (bedaquiline) is mixed with citric acid and a suitable solvent or with a mixture of solvents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZPV2015-391 | 2015-06-09 | ||
| CZ2015-391A CZ2015391A3 (en) | 2015-06-09 | 2015-06-09 | Salt of bedaquiline with citric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016198031A1 true WO2016198031A1 (en) | 2016-12-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2016/000063 Ceased WO2016198031A1 (en) | 2015-06-09 | 2016-06-03 | A salt of bedaquiline with citric acid |
Country Status (2)
| Country | Link |
|---|---|
| CZ (1) | CZ2015391A3 (en) |
| WO (1) | WO2016198031A1 (en) |
Citations (4)
| 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 |
| WO2016058564A1 (en) * | 2014-10-16 | 2016-04-21 | Zentiva, K.S. | Salts of bedaquiline |
-
2015
- 2015-06-09 CZ CZ2015-391A patent/CZ2015391A3/en unknown
-
2016
- 2016-06-03 WO PCT/CZ2016/000063 patent/WO2016198031A1/en not_active Ceased
Patent Citations (5)
| 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 |
| WO2016058564A1 (en) * | 2014-10-16 | 2016-04-21 | Zentiva, K.S. | Salts of bedaquiline |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ2015391A3 (en) | 2016-12-21 |
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