Stable monohydrate form of avibactam sodium salt and preparation method thereof

Abstract

The invention relates to an industrially useful and pharmaceutically stable avibactam sodium monohydrate and a preparation method thereof. The compounds of the invention can be used as beta-lactamase inhibitors.

Description

Technical Field

[0001] The present invention relates to an industrially useful and pharmaceutically stable monohydrate of avibactam sodium salt and a preparation method thereof. Background Art

[0002] WO2002 / 10172 describes azabicyclic compounds and salts thereof.

[0003] WO 2003 / 063864 describes the use as β-lactamase inhibitors and the use of said β-lactamase inhibitors in combination with β-lactam antibiotics (eg ceftazidime).

[0004] According to WO2011 / 042560 A1, the sodium salt of (1R,2S,5R)-7-oxo-6-sulfonyloxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide of Chemical Formula 1 (avibactam sodium salt) is described as an anhydrate form "B", "D", a monohydrate form "A", a dihydrate form "E", and an anhydrate form "C" is observed only as a mixture with the "A" form.

[0005]

[0006] [Chemical formula 1]

[0007] According to WO2011 / 042560 A1, the anhydrate form "D" is difficult to prepare industrially due to filterability problems caused by fine particles, and the dihydrate form "E" tends to lose water and hydrolyze during long-term storage and at higher temperatures. Although the anhydrate form "B" and the monohydrate form "A" are mentioned as preferred forms, when the "A" form is used as a seed, the "B" form can be stably obtained, and when the "A" form is used as a seed, the "A" form can also be stably obtained. Therefore, it is judged that the "A" form, the "B" form, the "D" form, and the "E" form are difficult to prepare industrially. Summary of the invention

[0008] 1. Technical issues to be resolved

[0009] The present invention is an invention for solving the above-mentioned problems, and an object of the present invention is to provide an industrially useful and pharmaceutically stable avibactam sodium salt monohydrate and a method for preparing the same.

[0010] (II) Technical solution

[0011] The present invention has found that a novel monohydrate form of the sodium salt (hereinafter referred to as the "α" form) can be prepared by an industrially efficient and effective process and is a pharmaceutically stable form compared to the existing monohydrate form "A".

[0012] In more detail, the compound of the present invention does not have filterability problems caused by fine particles like the "D" form, and can be prepared without using seed crystals like the "B" form, and is more pharmaceutically stable than the "B" form. In addition, unlike the "E" form and the "A" form, the compound of the present invention is a pharmaceutically stable crystalline form.

[0013] In particular, in the present invention, the "α" form of the present invention was confirmed to be a novel monohydrate in a different form from the existing monohydrate form "A" described in WO2011 / 042560 A1 by physicochemical property analysis, and the novel monohydrate "α" form of the present invention was found to be a more stable form in comparison of accelerated stability (40°C, relative humidity of 75%) experiments. In addition, it was confirmed that the "α" form remained in the monohydrate form in the accelerated stability (40°C, relative humidity of 75%) experiment.

[0014] The present invention provides a novel crystalline form "α" of avibactam sodium salt monohydrate having an X-ray diffraction pattern comprising characteristic peaks at 2θ of 10.0±0.5°, 15.0±0.5°, 16.0±0.5° and 19.4±0.5°.

[0015] More specifically, the present invention provides a novel crystalline form "α" of avibactam sodium salt monohydrate having an X-ray diffraction pattern comprising characteristic peaks at 2θ of 10.0±0.5°, 13.2±0.5°, 14.2±0.5°, 15.0±0.5°, 16.0±0.5°, 18.0±0.5° and 19.4±0.5°.

[0016] The present invention also provides a method for preparing the novel crystal form "α" of the monohydrate. Specifically, the present invention provides a method for preparing avibactam sodium salt monohydrate crystals, the preparation method comprising the following steps: (a) adding a solution of sodium 2-ethylhexanoate to a solution of tetrabutylammonium salt of avibactam; (b) stirring the reaction mixture of step (a) at room temperature and then at -10°C to -5°C to generate crystals; and (c) isolating the crystals.

[0017] Preferably, the preparation method of the present invention does not include the addition of seeds of avibactam sodium salt monohydrate.

[0018] In the preparation method of the present invention, the solution of the tetrabutylammonium salt of avibactam can be a solution of the tetrabutylammonium salt of avibactam in a mixed solvent of C1-C4 alcohol and water. The mixed solvent of C1-C4 alcohol and water can preferably be a mixed solvent of methanol and water. The mixed solvent of methanol and water can be a mixed solvent with a volume ratio of methanol: water of 4 to 8: 1, preferably a mixed solvent with a volume ratio of methanol: water of about 5.5: 1.

[0019] In the preparation method of the present invention, the solution of sodium 2-ethylhexanoate can be a solution of sodium 2-ethylhexanoate in a mixed solvent of C1-C4 alcohol or C1-C4 alcohol and water. The C1-C4 alcohol or the mixed solvent of C1-C4 alcohol and water can be methanol or a mixed solvent of methanol and water, respectively.

[0020] In the preparation method of the present invention, step (c) can be performed by washing the crystals obtained after filtering the mixture in step (b) with acetone at a temperature of 0°C to 5°C, for example, at a temperature of about 5°C, and then drying.

[0021] (III) Beneficial effects

[0022] The present invention provides an industrially useful and pharmaceutically stable novel monohydrate form "α" of avibactam sodium salt, which can be used as a β-lactamase inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : is a graph showing the results of a purity comparison experiment in an accelerated stability (40°C, 75% relative humidity) experiment of the novel monohydrate form "α" of the present invention, the monohydrate form "A" mentioned in WO2011 / 042560 A1, and the anhydrate form "B".

[0024] Figure 2 It is a graph showing the results of a comparative experiment on property changes in an accelerated stability (40°C, 75% relative humidity) experiment of the novel monohydrate form "α" of the present invention, the monohydrate form "A" mentioned in WO2011 / 042560 A1, and the anhydrate form "B".

[0025] Figure 3 Graph showing the results of an accelerated stability (40° C., 75% relative humidity) experiment to confirm the change in moisture content of the novel monohydrate form “α” of the present invention.

[0026] Figure 4 : This is the XRD pattern of the novel monohydrate form "α" of the present invention.

[0027] Figure 5This is the TGA spectrum of the novel monohydrate form "α" of the present invention.

[0028] Figure 6 This is the DSC spectrum of the novel monohydrate form "α" of the present invention. DETAILED DESCRIPTION

[0029] The present invention is illustrated by the following examples.

[0030] Example 1: Preparation of the novel monohydrate form "α" of avibactam sodium

[0031]

[0032] To the solution of the tetrabutylammonium salt of avibactam (17.64 g, 34.2 mmol) in a mixed solution of methanol (110 ml) and purified water (20 ml), a solution of 2-ethylhexanoic acid sodium (11.57 g, 69.6 mmol) in methanol (50 ml) was added for 45 minutes. The reaction mixture obtained was stirred at room temperature for about 1 hour, and then stirred overnight at about -10 ° C to -5 ° C. After filtering the mixture, the obtained crystals were washed with acetone (50 ml) at 5 ° C and dried in vacuo to obtain a novel monohydrate form "α" (6.5 g, a yield of 75.4%).

[0033] Example 2. Comparative experiment on accelerated stability (40°C, 75% relative humidity) of purity / property changes

[0034] The novel monohydrate form "α", monohydrate form "A" and anhydrous form "B" of the sodium salt of avibactam prepared in Example 1 were packaged in glass bottles, respectively, and stored at 40°C and 75% relative humidity for 6 weeks while measuring the purity change by HPLC every week. The comparative experimental results are shown in Figure 1 and Figure 2 The novel monohydrate according to the present invention was found to be a more stable form than the monohydrate form "A" mentioned in WO2011 / 042560 A1.

[0035] Example 3. Accelerated stability test of moisture content change (40°C, relative humidity 75%)

[0036] The novel monohydrate form "α" of the sodium salt of avibactam prepared in Example 1 was packaged in a glass bottle and stored at 40°C and 75% relative humidity for 6 weeks while measuring the change in moisture content using a Karl Fischer titrator every week for about 6 weeks. The results are shown in Figure 3 It was confirmed that the novel monohydrate according to the present invention remained in the monohydrate form in an accelerated stability (40° C., relative humidity of 75%) experiment.

[0037] Example 4. Measurement of XRD spectrum

[0038] The novel monohydrate form "α" of the sodium salt of avibactam prepared in Example 1 was confirmed by X-ray powder diffraction in an apparatus with copper Kα radiation. The un-crushed sample was placed on a plate and analyzed at 2θ angles of 5-50°. The results are shown in Figure 4 This has different physicochemical properties from the existing monohydrate form "A" with characteristic peaks of 8.5, 15.3, 16.4, 17.0, 24.3.

[0039] Example 5. Measurement of TGA spectrum

[0040] The TGA spectrum was measured while heating 3-5 mg of the novel monohydrate form "α" of the sodium salt of avibactam prepared in Example 1 from 30°C to 500°C at a rate of 10K / min. As a result, it was confirmed that a weight loss of 5.57% was shown at 100-140°C, which is a monohydrate corresponding to the theoretical water content of 5.90% of the monohydrate. In addition, decomposition exotherm accompanied by weight loss at 200-220°C was confirmed, and the results are shown in Figure 5 middle.

[0041] Example 6. Measurement of DSC spectrum

[0042] 3-5 mg of the novel monohydrate form "α" of the sodium salt of avibactam prepared in Example 1 was heated from 25°C to 500°C at a rate of 10K / min while measuring the DSC spectrum. As a result, an exothermic decomposition peak at 227.3°C was confirmed. WO2011 / 042560 A1 records that the exothermic decomposition peak of the monohydrate form A is 238.9°C. It was confirmed that this has different physicochemical properties from the existing monohydrate form "A", and the results are shown in Figure 6 middle.

Claims

1. A crystal of avibactam sodium salt monohydrate, which has an X-ray diffraction pattern comprising characteristic peaks at 2θ of 10.0±0.5°, 15.0±0.5°, 16.0±0.5° and 19.4±0.5°.

2. The avibactam sodium salt monohydrate crystal according to claim 1, wherein The avibactam sodium salt monohydrate crystals have an X-ray diffraction pattern including characteristic peaks at 2θ values ​​of 10.0±0.5°, 13.2±0.5°, 14.2±0.5°, 15.0±0.5°, 16.0±0.5°, 18.0±0.5° and 19.4±0.5°.

3. A method for preparing avibactam sodium salt monohydrate crystals, comprising the following steps: (a) adding a solution of sodium 2-ethylhexanoate to a solution of tetrabutylammonium salt of avibactam; (b) stirring the reaction mixture of step (a) at room temperature and then at -10°C to -5°C to generate crystals; and (c) isolating the crystals.

4. The preparation method according to claim 3, characterized in that: The preparation method does not include the addition of seed crystals of avibactam sodium salt monohydrate.

5. The preparation method according to claim 3, characterized in that: The solution of tetrabutylammonium salt of avibactam is a solution of tetrabutylammonium salt of avibactam in a mixed solvent of methanol and water.

6. The preparation method according to claim 5, characterized in that: The mixed solvent of methanol and water is a mixed solvent with a volume ratio of methanol:water of 4 to 8:

1.

7. The preparation method according to claim 3, characterized in that: The solution of sodium 2-ethylhexanoate is a solution of sodium 2-ethylhexanoate in methanol or a mixed solvent of methanol and water.

8. The preparation method according to claim 3, characterized in that: The step (c) is performed by washing the crystals obtained after filtering the mixture of the step (b) with acetone at a temperature of 0°C to 5°C and then drying.

9. The preparation method according to claim 3, characterized in that: The avibactam sodium salt monohydrate crystals have an X-ray diffraction pattern including characteristic peaks at 2θ of 10.0±0.5°, 15.0±0.5°, 16.0±0.5° and 19.4±0.5°.

10. The preparation method according to claim 3, characterized in that: The avibactam sodium salt monohydrate crystals have an X-ray diffraction pattern including characteristic peaks at 2θ values ​​of 10.0±0.5°, 13.2±0.5°, 14.2±0.5°, 15.0±0.5°, 16.0±0.5°, 18.0±0.5° and 19.4±0.5°.

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