Organic solvent-free dihydrate of fosravuconazole L-lysine salt and method for producing the same
The production of an organic solvent-free dihydrate form of fosravuconazole L-lysine salt addresses the instability issue of ethanol-containing forms by maintaining a stable crystalline structure, enhancing storage stability through controlled precipitation in a solvent-free environment.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- TOKUYAMA CORP
- Filing Date
- 2024-11-21
- Publication Date
- 2026-06-02
Smart Images
Figure 2026090012000001_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to an organic solvent-free solvate of fostrabconazole L-lysine salt and a method for producing the same.
Background Art
[0002] Fostrabconazole L-lysine ethanol adduct is useful as a therapeutic agent for onychomycosis. The fostrabconazole L-lysine ethanol adduct is represented by the following formula.
[0003]
Chemical Formula
Prior Art Documents
Patent Documents
[0004]
Patent Document 1
Summary of the Invention
Problems to be Solved by the Invention
[0005] An object of the present invention is to provide an organic solvent-free solvate of fostrabconazole L-lysine salt in a novel crystal form and a method for producing the same.
Means for Solving the Problems
[0006] According to one aspect, an organic solvent-free solvate of fostrabconazole L-lysine salt is provided.
[0007] According to another aspect, a method for producing an organic solvent-free solvate of fostrabconazole L-lysine salt is provided. This production method includes dissolving fostrabconazole and L-lysine in water and ethanol to obtain a first mixed solution within a range of pH 5.0 or more and pH 5.7 or less, and precipitating crystals of the organic solvent-free solvate of fostrabconazole L-lysine salt from the first mixed solution.
Effects of the Invention
[0008] The present invention provides a novel crystalline form of fosravuconazole L-lysine salt, an organic solvent-free dihydrate, and a method for producing the same. [Brief explanation of the drawing]
[0009] [Figure 1] X-ray diffraction pattern of the organic solvent-free dilution of fosravuconazole L-lysine salt obtained in Example 1. [Figure 2] X-ray diffraction pattern of the fosravuconazole L-lysine ethanol adduct obtained in Comparative Example 1. [Figure 3] Nuclear magnetic resonance spectra of the organic solvent-free dihydrate of fosravuconazole L-lysine salt obtained in Example 1. [Figure 4] Nuclear magnetic resonance spectrum of the fosravuconazole L-lysine ethanol adduct obtained in Comparative Example 1. [Modes for carrying out the invention]
[0010] According to one embodiment, an organic solvent-free dihydrate of fosravuconazole L-lysine salt is provided. The organic solvent-free dihydrate of fosravuconazole L-lysine salt is a type of crystalline form of fosravuconazole L-lysine salt, and is a crystal that contains almost no organic solvent molecules. The organic solvent-free dihydrate of fosravuconazole L-lysine salt is useful as a treatment for onychomycosis, similar to fosravuconazole L-lysine ethanol adduct.
[0011] As mentioned above, a known crystalline form of fosravuconazole L-lysine salt is the fosravuconazole L-lysine ethanol adduct, which is obtained by adding or solvating one molecule of ethanol to fosravuconazole L-lysine salt. Because this fosravuconazole L-lysine ethanol adduct contains ethanol, the ethanol volatilizes at room temperature, which can change its crystalline form. In contrast, the organic solvent-free dihydrogen fosravuconazole L-lysine salt contains almost no organic solvents, so its crystalline form is less prone to change, and it has excellent storage stability.
[0012] The following describes the details of the organic solvent-free dihydrate of fosravuconazole L-lysine salt.
[0013] <Fosravuconazole L-lysine salt in an organic solvent-free form> The organic solvent-free dihydrate of fosravuconazole L-lysine salt can be a solid crystal at room temperature.
[0014] The organic solvent-free fosravuconazole L-lysine salt hydrate may also be a hydrate of fosravuconazole L-lysine salt, or it may be a crystal consisting only of fosravuconazole L-lysine salt and free from crystal water and crystal solvent.
[0015] The organic solvent-free dihydrate of fosravuconazole L-lysine salt may inevitably contain residual organic solvents. Examples of such organic solvents include at least one compound selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, acetone, and acetonitrile. Preferably, the organic solvent is at least one selected from the group consisting of ethanol and acetone.
[0016] In the organic solvent-free dihydrate of fosravuconazole L-lysine salt, the amount of organic solvent per mole of fosravuconazole is, for example, 0.4 moles or less, preferably 0.2 moles or less, and more preferably 0.1 moles or less. There is no particular lower limit for the amount of organic solvent, but in one example it is 0.01 moles or more, and in another example it is 0.001 moles or more.
[0017] In the organic solvent-free dihydrate of fosravuconazole L-lysine salt, the content of organic solvents determined by gas chromatography is, for example, 0.50% by mass or less. The organic solvent content is preferably 0.10% by mass or less, more preferably 0.050% by mass or less, and even more preferably 0.020% by mass or less. There is no particular lower limit for the organic solvent content, but according to one example, it is below the detection limit of the measuring device, and according to another example, it is 0.010% by mass or more.
[0018] The powder X-ray diffraction (XRD) pattern of the non-solvated form of voriconazole L-lysine salt has peaks within the range of diffraction angles represented by 2θ of, for example, 7.5° or more and 7.9° or less, 8.0° or more and 8.4° or less, 16.4° or more and 16.8° or less, 19.8° or more and 20.2° or less, and 23.9° or more and 24.2° or less.
[0019] The proton nuclear magnetic resonance spectrum of the non-solvated form of voriconazole L-lysine salt has peaks within the range of, for example, 8.8 or more and 9.1 ppm or less (s, 1H), 7.7 or more and 8.0 ppm or less (m, 6H), 7.1 or more and 7.4 ppm or less (m, 1H), 6.9 or more and 7.1 ppm or less (m, 1H), 6.8 or more and 7.0 ppm or less (m, 1H), 5.1 or more and 5.4 ppm or less (m, 4H), 3.9 or more and 4.0 ppm or less (q, 1H), 3.7 or more and 3.8 ppm or less (t, 1H), 3.0 or more and 3.1 ppm or less (t, 2H), 1.8 or more and 2.0 ppm or less (m, 2H), 1.7 or more and 1.8 ppm or less (m, 2H), 1.4 or more and 1.6 ppm or less (m, 2H), and 1.3 or more and 1.4 ppm or less (d, 2H).
[0020] <Method for producing non-solvated form of voriconazole L-lysine salt> The non-solvated form of voriconazole L-lysine salt according to the embodiment can be obtained, for example, by dissolving voriconazole and L-lysine in water and an organic solvent to obtain a first mixture within the range of pH 5.0 or more and pH 5.7 or less, and precipitating crystals of the non-solvated form of voriconazole L-lysine salt from the first mixture.
[0021] In other words, by using water and an organic solvent as solvents to dissolve fosravuconazole and L-lysine, and controlling the pH of the resulting solution within the range of pH 5.0 to pH 5.7, crystals of the organic solvent-free fosravuconazole L-lysine salt can be precipitated. If the pH of the first mixture falls outside this range, crystals of the organic solvent-free fosravuconazole L-lysine salt cannot be obtained, and the solution may become the organic solvent-based fosravuconazole L-lysine salt. Furthermore, if water is not present and only an organic solvent is used, crystals of the organic solvent-free fosravuconazole L-lysine salt cannot be obtained, and the solution may become the organic solvent-based fosravuconazole L-lysine salt. The pH of the first mixture can be measured, for example, with a pH meter.
[0022] Fosravuconazole can be manufactured by known methods.
[0023] L-lysine is, for example, in solid form. Alternatively, an aqueous solution of L-lysine, obtained by dissolving L-lysine in water, may be used. The L-lysine concentration in the aqueous solution is, for example, 10% by mass or more and 50% by mass or less.
[0024] The amount of L-lysine relative to 1 mole of fosravuconazole is, for example, 0.5 moles or more and 3.0 moles, preferably 1.0 mole or more and 1.5 moles or less.
[0025] The amount of water per 1 g of fosravuconazole is, for example, 0.1 mL to 10 mL. Preferably, the amount of water is 0.5 mL to 5 mL, and more preferably 0.7 mL to 3 mL.
[0026] The amount of organic solvent per 1 g of fosravuconazole is, for example, 1 mL to 50 mL. Preferably, the amount of organic solvent is 10 mL to 30 mL, and more preferably 15 mL to 25 mL.
[0027] The ratio V1 / V2 of the volume of the organic solvent V1 to the volume of water V2 is, for example, 5.7 to 49. The ratio V1 / V2 is preferably 10 to 30, and more preferably 15 to 25.
[0028] Examples of organic solvents include at least one compound selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, acetone, and acetonitrile. Preferably, the organic solvent is at least one selected from the group consisting of ethanol and acetone.
[0029] The contact temperature between fosravuconazole and L-lysine and water and organic solvent when preparing the first mixture is, for example, -10°C to 80°C, and preferably 0°C to 50°C.
[0030] An acid may be used as a pH adjuster for the first mixture. For example, at least one acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid may be used.
[0031] When preparing the first mixture, fosravuconazole and L-lysine may be mixed first, then water, an organic solvent, and optionally a pH adjuster may be added; or fosravuconazole may be mixed with water, an organic solvent, and optionally a pH adjuster, and then L-lysine may be added.
[0032] The precipitation temperature when precipitating the organic solvent-free dihydrate of fosravuconazole L-lysine salt from the first mixture is, for example, -10°C to 80°C, and preferably 0°C to 50°C.
[0033] Furthermore, adding seed crystals to the first mixture may promote the precipitation of the organic solvent-free dihydrate of fosravuconazole L-lysine salt.
[0034] The organic solvent-free dihydrate of fosravuconazole L-lysine salt precipitated by the above method may be separated, for example, by filtration, and then washed and dried. [Examples]
[0035] The present invention will be described in detail below with reference to examples, but the present invention can be controlled by these examples. It is not limited.
[0036] Furthermore, the powder X-ray diffraction measurements obtained in the examples and comparative examples, 1 The measurements using 1H nuclear magnetic resonance spectroscopy and the residual solvent were performed using the following method.
[0037] <Measurement of crystal form> Equipment: Powder X-ray diffractometer Model: D2 PHASER (Bruker) Measurement method: ASC6 BB Dtex X-ray output: 30kV-10mA Step width: 0.02° Tube:Cu < 1 Measurement of H nuclear magnetic resonance spectrum > Equipment: Nuclear magnetic resonance spectrometer Model: JNM-ECZ600G (manufactured by JEOL) Measured radionuclides: 1 H Magnetic field strength: 14.1T <Measurement of residual solvent> Equipment: Headspace gas chromatography Model: Agilent 7890B (manufactured by Agilent Technologies) Agilent 7697A (manufactured by Agilent Technologies) Detector: Flame ionization detector (FID) Column: Agilent Technologies DB-624 (length 30m, inner diameter 0.5) (30mm, film thickness: 3.00μm) Column temperature: After injection at a constant temperature of around 40°C, it was maintained for 5 minutes, then the temperature was increased at a rate of 10°C per minute to 260°C, and maintained at 260°C for 5 minutes. Detector temperature: 260℃ Carrier gas: He Linear speed: 29.4cm / s Headspace oven temperature: 90℃ Loop temperature: 125℃ Transfer line temperature: 130℃ Vial equilibration time: 30 minutes <Example 1> Dissolve 10 g (18 mmol) of fosravuconazole and 3.7 g (1.4 eq.) of L-lysine in 10 mL of water, and adjust the pH to 5.7 by adding acetic acid dropwise. Add 200 mL of ethanol dropwise, and stir the solution at 40°C for 4 hours and at room temperature for 18 hours. Filter off the precipitated crystals to obtain 10.2 g of fosravuconazole L-lysine salt in an organic solvent-free solution.
[0038] Powder X-ray diffraction of the organic solvent-free fosravuconazole L-lysine salt solution was measured, and diffraction peaks were observed at 7.7°, 8.2°, 16.6°, 20.0°, and 24.1°. Figure 1 shows the X-ray diffraction pattern of the organic solvent-free fosravuconazole L-lysine salt solution obtained in Example 1.
[0039] Nuclear magnetic resonance spectra of the organic solvent-free fosravuconazole L-lysine salt were measured, revealing peaks at 8.9 ppm (s,1H), 7.7-8.0 ppm (m,6H), 7.1-7.4 ppm (m,1H), 6.9-7.1 ppm (m,1H), ≤6.8-7.0 ppm (m,1H), 5.1-5.4 ppm (m,4H), 3.9 ppm (q,1H), 3.7 ppm (t,1H), 3.0 ppm (t,2H), 1.8-2.0 ppm (m,2H), 1.7-1.8 ppm (m,2H), 1.4-1.6 ppm (m,2H), and 1.4 ppm (d,2H). Figure 3 shows the nuclear magnetic resonance spectrum of the organic solvent-free dihydrate of fosravuconazole L-lysine salt obtained in Example 1.
[0040] Headspace gas chromatography analysis of the residual solvent in the organic solvent-free dihydrate of fosravuconazole L-lysine salt revealed the presence of 0.10% ethanol.
[0041] <Example 2> 9.8 g of fosravuconazole L-lysine salt was obtained in the same manner as in Example 1, except that the pH of the aqueous solution was adjusted to 5.2 with acetic acid. <Example 3> 10.1 g of fosravuconazole L-lysine salt was obtained in the same manner as in Example 1, except that the pH of the aqueous solution was adjusted to 5.0 with acetic acid.
[0042] <Example 4> 9.2 g of fosravuconazole L-lysine salt was obtained in the same manner as in Example 1, except that the pH of the aqueous solution was adjusted to 5.3 with acetic acid and methanol was used instead of ethanol.
[0043] <Example 5> 10.5 g of fosravuconazole L-lysine salt was obtained in the same manner as in Example 1, except that the pH of the aqueous solution was adjusted to 5.2 with acetic acid and acetone was used instead of ethanol.
[0044] <Comparative Example 1> 10.9 g of fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that the pH of the aqueous solution was adjusted to 4.5 with acetic acid. Powder X-ray diffraction of the fosravuconazole L-lysine ethanol adduct was measured, and diffraction peaks were observed at 9.0°, 10.1°, 14.8°, 16.1°, 17.5°, 12.7°, 20.9°, and 24.3°. Figure 2 shows the X-ray diffraction pattern of the organic solvent-free fosravuconazole L-lysine salt obtained in Comparative Example 1.
[0045] Nuclear magnetic resonance (M / E) spectra of fosravuconazole L-lysine ethanol adduct were measured and found to be 8.6 ppm (s, 1H), 7.8-7.9 ppm (m, 6H), 7.2-7.3 ppm (m, 1H), 6.9-7.0 ppm (m, 1H), ≤6.8-6.9 ppm (m, 1H), 5.2-5.4 ppm (m, 2H), and 5.2 ppm. Peaks were observed at m(q,2H), 3.9 ppm(q,1H), 3.7 ppm(t,1H), 3.6 ppm(q,2H), 3.0 ppm(t,2H), 1.8-1.9 ppm(m,2H), 1.7-1.8 ppm(m,2H), 1.4-1.6 ppm(m,2H), 1.3 ppm(d,2H), and 1.2 ppm(t,3H). Figure 4 shows the nuclear magnetic resonance spectrum of the organic solvent-free fosravuconazole L-lysine salt obtained in Comparative Example 1.
[0046] Headspace gas chromatography analysis of the residual solvent in the fosravuconazole L-lysine ethanol adduct revealed the presence of 6.2% ethanol.
[0047] <Comparative Example 2> 10 g (18 mmol) of fosravuconazole and 3.7 g (1.4 eq.) of L-lysine were mixed with 100 mL of methanol, and acetic acid was added dropwise to adjust the pH to 5.0. 200 mL of ethanol was added dropwise, and the mixture was stirred at 40°C for 4 hours and at room temperature for 18 hours. The precipitated crystals were filtered off to obtain 10.4 g of fosravuconazole-L-lysine ethanol adduct.
[0048] [Table 1]
[0049] The following are some of the favorable aspects of the invention. [1] A fosravuconazole L-lysine salt dihydrogenated without organic solvents. [2] The organic solvent-free dihydrate of the L-lysine salt described in [1], wherein the content of organic solvents determined by gas chromatography is 0.50% by mass or less. [3] An organic solvent-free dihydrate of the L-lysine salt described in [1] or [2], having peaks in the powder X-ray diffraction pattern within the ranges of 7.5° to 7.9°, 8.0° to 8.4°, 16.4° to 16.8°, 19.8° to 20.2°, and 23.9° to 24.2°. [4] In the nuclear magnetic resonance spectrum of protons, the following ranges were observed: 8.8 to 9.1 ppm (s,1H), 7.7 to 8.0 ppm (m,6H), 7.1 to 7.4 ppm (m,1H), 6.9 to 7.1 ppm (m,1H), 6.8 to 7.0 ppm (m,1H), 5.1 to 5.4 ppm (m,4H), 3.9 to 4.0 ppm (q,1H), 3.7 An organic solvent-free dihydrate of an L-lysine salt according to any one of [1] to [3], having peaks within the ranges of 3.8 ppm or less (t,1H), 3.0 to 3.1 ppm (t,2H), 1.8 to 2.0 ppm (m,2H), 1.7 to 1.8 ppm (m,2H), 1.4 to 1.6 ppm (m,2H), and 1.3 to 1.4 ppm (d,2H). [5] The first mixture is obtained by dissolving fosravuconazole and L-lysine in water and an organic solvent, with a pH in the range of 5.0 to 5.7. Precipitating crystals of an organic solvent-free dihydrate of fosravuconazole L-lysine salt from the first mixture, A method for producing an organic solvent-free dihydrate of fosravuconazole L-lysine salt, which contains the above. [6] The manufacturing method according to [5], wherein the ratio V1 / V2 of the volume V1 of the organic solvent to the volume V2 of the water is 5.7 or more and 49 or less. [7] The manufacturing method according to [5] or [6], wherein the amount of water per 1 g of fosravuconazole is 0.1 mL or more and 10 mL or less. [8] The manufacturing method according to any one of [5] to [7], wherein the organic solvent is at least one selected from the group consisting of ethanol and acetone.
Claims
1. A fosravuconazole L-lysine salt dihydrogenated without organic solvents.
2. The organic solvent-free dihydrate of L-lysine salt according to claim 1, wherein the content of organic solvents determined by gas chromatography is 0.50% by mass or less.
3. The organic solvent-free dihydrate of L-lysine salt according to claim 1, wherein the powder X-ray diffraction pattern has peaks in the ranges of 7.5° to 7.9°, 8.0° to 8.4°, 16.4° to 16.8°, 19.8° to 20.2°, and 23.9° to 24.2°.
4. In the nuclear magnetic resonance spectrum of protons, the values were 8.8 to 9.1 ppm (s, 1H), 7.7 to 8.0 ppm (m, 6H), 7.1 to 7.4 ppm (m, 1H), 6.9 to 7.1 ppm (m, 1H), 6.8 to 7.0 ppm (m, 1H), 5.1 to 5.4 ppm (m, 4H), and 3.9 to 4.0 ppm (q, 1H). The organic solvent-free dihydrate of L-lysine salt according to claim 1, having peaks in the following ranges: 3.7 to 3.8 ppm (t, 1H), 3.0 to 3.1 ppm (t, 2H), 1.8 to 2.0 ppm (m, 2H), 1.7 to 1.8 ppm (m, 2H), 1.4 to 1.6 ppm (m, 2H), and 1.3 to 1.4 ppm (d, 2H).
5. The first mixture is obtained by dissolving fosravuconazole and L-lysine in water and an organic solvent, with a pH in the range of 5.0 to 5.
7. Precipitating crystals of an organic solvent-free dihydrate of fosravuconazole L-lysine salt from the first mixture, A method for producing an organic solvent-free dihydrate of fosravuconazole L-lysine salt, which contains the above.
6. The manufacturing method according to claim 5, wherein the ratio V1 / V2 of the volume V1 of the organic solvent to the volume V2 of the water is 5.7 or more and 49 or less.
7. The manufacturing method according to claim 5, wherein the amount of water per 1 g of fosravuconazole is 0.1 mL or more and 10 mL or less.
8. The manufacturing method according to claim 5, wherein the organic solvent is at least one selected from the group consisting of ethanol and acetone.