WO2023137966A1 - New crystal form of delafloxacin meglumine and preparation method therefor - Google Patents

Abstract

The present invention provides a new crystal form of delafloxacin meglumine and a preparation method therefor. An X-ray powder diffraction pattern thereof has diffraction peaks at the following angles of 2θ: 7.323 ±0.2º, 8.079 ±0.2º, 8.377 ±0.2º, 9.539 ±0.2º, 15.139 ±0.2º and 18.422 ±0.2º. The preparation method therefor comprises the following steps: taking a crude product of delafloxacin meglumine and dissolving same in a mixed solvent of alcohol and an ester/ketone/ether/alkane, stirring same, performing membrane filtering, precipitating a solid therefrom, filtering same, and drying the material so as to obtain the new type crystal form of delafloxacin meglumine. The new crystal form of delafloxacin meglumine provided by the present invention has good preparation stability and storage stability, and can adapt to environmental conditions of wider manufacturing, storage and transportation; and a preparation thereof can better withstand problems such as uneven pharmaceutical active ingredients and reduced purity which may be generated by factors of temperature, humidity, crystal form change, etc., reducing the risk of a reduction in efficacy and safety risks brought about thereby, thus being more suitable for being applied to tablets and industrialization, and has high industrial application and economic value.

Description

A new crystal form of delafloxacin meglumine salt and its preparation method

This application claims the priority of the Chinese patent application submitted to the China Patent Office on January 20, 2022, with the application number 202210066268.X and the application name "A new crystal form of delafloxacin meglumine salt and its preparation method", the entire content of which is incorporated in this application by reference.

technical field

The invention relates to the technical field of pharmaceutical crystal forms, in particular to a new crystal form of delafloxacin meglumine salt and a preparation method thereof.

Background technique

Since the discovery of norfloxacin in the late 1970s, fluoroquinolones have developed rapidly, and a large number of products have been launched.

Delafloxacin (English name: Delafloxacin) is a fluoroquinolone compound with a new structure developed by Yuyong Pharmaceutical Co., Ltd. in Japan. Its chemical name is 1-(6-amino-3,5-difluoro-2-pyridyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid. Its chemical structure is shown in the following formula I:

The chemical structure of its meglumine salt is shown in the following formula II:

Delafloxacin (English name: Delafloxacin) is a new generation of broad-spectrum fluoroquinolone antibacterial agent with excellent broad-spectrum antibacterial activity and bactericidal activity. Its target is bacterial DNA topoisomerase. Compared with other quinolone antibacterial agents, it is more effective against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus, which is resistant to other quinolone antibacterial agents. At present, it has been officially approved by the US FDA for marketing. The product name is Baxdela, which is used to treat bacterial skin and skin structure infections. Its marketed dosage forms include tablets, and its marketed form is delafloxacin meglumine salt. Therefore, the research on the crystal form of delafloxacin meglumine salt is of great significance to the development of its tablet.

PCT application WO2006042034A2 disclosed delafloxacin meglumine salt anhydrate crystal form and delafloxacin meglumine salt trihydrate crystal form and their preparation methods, and characterized by XRPD, but the applicant found that the delafloxacin meglumine salt anhydrate crystal form and delafloxacin meglumine salt trihydrate crystal form disclosed in WO2006042034A2 had the following defects:

1. Since the anhydrous crystal form of delafloxacin meglumine salt and the trihydrate crystal form of delafloxacin meglumine salt disclosed in PCT application WO2006042034A2 and their preparation methods are the anhydrous crystal form of delafloxacin meglumine salt and the trihydrate crystal form of delafloxacin meglumine salt prepared from the same solvent system, so most of the products appear in the mixed form of delafloxacin meglumine salt anhydrate crystal form and delafloxacin meglumine salt trihydrate crystal form, making Delafloxacin meglumine salt anhydrate crystal form and delafloxacin meglumine salt trihydrate crystal form have poor preparation repeatability, poor preparation stability and are not suitable for industrial production;

2. The anhydrate crystal form of delafloxacin meglumine salt is easy to absorb moisture and will convert into the trihydrate crystal form in a high-humidity environment, which has poor storage stability, so that the tablets prepared from the anhydrate crystal form of delafloxacin meglumine salt may have problems such as unstable storage, unstable active ingredient content, increased impurity content during storage, poor production reproducibility, decreased drug efficacy, and poor product quality stability;

3. The DSC spectrum of Comparative Example 2 of the present application shows that the trihydrate crystal form is thermally unstable, and will undergo crystal transformation at 120° C., transforming into an anhydrate crystal form.

PCT application WO2014138639A1 discloses delafloxacin meglumine salt crystal forms Form 1A and Form1B and their preparation methods, and is characterized by XRPD and DSC; PCT application WO2014138639A1 also discloses that delafloxacin meglumine salt anhydrate crystal form described in WO2006042034A2 is actually a mixture of Form 1A and Form 1B. The applicant found that Form 1A and Form 1B disclosed in WO2014138639A1 have the following defects:

1. The European drug specification for delafloxacin meglumine salt discloses that Form 1A is a variable hemihydrate, which will transform into a trihydrate in a high-humidity environment, and has poor stability; Form 1B is a metastable crystal form, and Form 1B will be converted into Form 1A when exposed to specific humidity and high temperature; this makes the tablets prepared from Form 1A and Form 1B may have unstable storage, poor production reproducibility, unstable active ingredient content, and increased impurity content during storage. Decreased drug efficacy, poor product quality stability, etc.;

2. Form 1B is obtained by drying and transforming the trihydrate crystal form under low humidity conditions. The preparation conditions are harsh and the process improvement is difficult, so it is not suitable for industrial scale production;

3. Form 1A is obtained from the trihydrate crystal form after being dried under vacuum conditions, exposed to high temperature and humidity, and crystallized. The preparation conditions are harsh and the process improvement is difficult, so it is not suitable for industrial scale production.

In summary, the existing crystal form of delafloxacin meglumine salt is not suitable for industrial-scale production, nor is it suitable for use as an active ingredient in tablets to prepare tablets that meet the registration standards. Therefore, it is necessary to develop a new crystal form of delafloxacin meglumine salt with high crystallinity, good bioavailability, good stability, good production reproducibility, good amplification effect, not easy to absorb moisture, good compressibility, low residual solvents, high chemical purity, suitable for use in tablets and industrialization. .

Contents of the invention

Aiming at the deficiencies in the prior art, the object of the present invention is to solve the problems existing in the existing crystal form of delafloxacin meglumine salt by providing a new crystal form of delafloxacin meglumine salt and a preparation method thereof. At the same time, the present invention also relates to the preparation method of the new crystal form, its pharmaceutical composition and application.

Compared with the existing crystal form of delafloxacin meglumine salt, the new crystal form has at least one of the following favorable properties: good stability, such as crystal form stability, thermal stability, chemical stability, mechanical stability, storage stability, etc.; good solubility; fast dissolution rate; good bioavailability; high crystallinity; good production reproducibility; good amplification effect; And compressibility, good appearance; improve bioavailability, drug efficacy of preparations; prolong the shelf life of preparations; suitable for the application of new dosage forms, etc.

Technical scheme of the present invention is as follows:

The first aspect of the present invention provides a new crystal form of delafloxacin meglumine salt, which is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 9.539±0.2°, 15.139±0.2°, 18.422±0.2°;

Further, according to the above-mentioned new crystal form of delafloxacin meglumine salt, it is also characterized in that its X-ray powder diffraction pattern also has one or more diffraction peaks at the following 2θ angles: 8.638±0.2°, 13.621±0.2°, 16.260±0.2°, 17.721±0.2°, 19.121±0.2°, 19.960±0.2°;

Preferably, the new crystal form of delafloxacin meglumine salt has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 8.638±0.2°, 9.539±0.2°, 15.139±0.2°, 18.422±0.2°, 16.260±0.2°, 17.72 1±0.2°;

More preferably, the new crystal form of delafloxacin meglumine salt has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 8.638±0.2°, 9.539±0.2°, 13.621±0.2°, 15.139±0.2°, 16.260±0.2°, 17.7 21±0.2°, 18.422±0.2°, 19.121±0.2°, 19.960±0.2°;

Further, according to the above-mentioned new crystal form of delafloxacin meglumine salt, it is also characterized in that its X-ray powder diffraction pattern also has one or more diffraction peaks at the following 2θ angles: 21.279±0.2°, 22.140±0.2°, 22.718±0.2°, 23.801±0.2°, 25.820±0.2°, 27.100±0.2°;

Preferably, the new crystal form of delafloxacin meglumine salt has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 8.638±0.2°, 9.539±0.2°, 13.621±0.2°, 15.139±0.2°, 16.260±0.2°, 17.72 1±0.2°, 18.422±0.2°, 19.121±0.2°, 19.960±0.2°, 22.718±0.2°, 25.820±0.2°, 27.100±0.2°;

More preferably, the new crystal form of delafloxacin meglumine salt has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 8.638±0.2°, 9.539±0.2°, 13.621±0.2°, 15.139±0.2°, 16.260±0.2°, 17.7 21±0.2°, 18.422±0.2°, 19.121±0.2°, 19.960±0.2°, 21.279±0.2°, 22.140±0.2°, 22.718±0.2°, 23.801±0.2°, 25.820±0.2°, 27.100±0.2°;

Most preferably, the new crystal form of delafloxacin meglumine salt has diffraction peaks at the following 2θ angles:

2θ	Relative Strength%
7.323±0.2°	39.0
8.079±0.2°	100.0
8.377±0.2°	25.3
8.638±0.2°	21.8
9.539±0.2°	22.3
10.919±0.2°	1.5
13.621±0.2°	3.5
15.139±0.2°	16.3
15.482±0.2°	1.7
16.260±0.2°	30.2
16.960±0.2°	2.0
17.721±0.2°	34.4
18.422±0.2°	18.0
19.121±0.2°	7.2
19.621±0.2°	4.7
19.960±0.2°	11.6
20.900±0.2°	1.5
21.279±0.2°	5.6
22.140±0.2°	2.6
22.718±0.2°	5.6
23.135±0.2°	1.5
23.801±0.2°	8.0
24.480±0.2°	4.8
25.379±0.2°	12.3
25.820±0.2°	30.3
26.198±0.2°	8.7

27.100±0.2°	17.2
27.641±0.2°	2.8
28.682±0.2°	2.1
28.980±0.2°	3.2
30.220±0.2°	4.9
32.117±0.2°	1.8
32.838±0.2°	2.3
33.240±0.2°	2.8
34.041±0.2°	2.3
36.220±0.2°	2.0
37.082±0.2°	1.2
37.800±0.2°	2.2
38.879±0.2°	4.0
39.941±0.2°	1.9
42.420±0.2°	2.1
43.362±0.2°	0.8
48.822±0.2°	1.1

In a particularly preferred embodiment of the present invention, the present invention provides a new crystal form of delafloxacin meglumine salt, which has an X-ray powder diffraction pattern that is substantially the same as that of Figure 8;

In an embodiment of the present invention, the new crystal form of delafloxacin meglumine salt provided by the present invention is basically anhydrous, and its solvent residue is less than 2.3% by weight, preferably less than 2.0% by weight, and its TGA diagram is shown in Figure 9 or Figure 11;

In an embodiment of the present invention, the new crystalline form of delafloxacin meglumine salt provided by the present invention has a melting point of about 230-232°C, preferably about 230°C or 232°C, and its DSC chart is shown in Figure 10 or Figure 12;

In a second aspect, the present invention provides a method for preparing a new crystal form of delafloxacin meglumine salt, comprising the following steps:

The crude product of delafloxacin meglumine salt is dissolved in a mixed solvent of alcohols and esters/ketones/ethers/alkanes, stirred, membrane filtered, solids are precipitated, filtered, and dried to obtain final product;

Further, according to the preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the crude product of delafloxacin meglumine salt can be delafloxacin meglumine salt amorphous form or delafloxacin meglumine salt crystal form, preferably delafloxacin meglumine salt anhydrate crystal form or delafloxacin meglumine salt trihydrate crystal form, more preferably delafloxacin meglumine salt anhydrate crystal form, more preferably WO20060 The delafloxacin meglumine salt anhydrate crystal form described in 42034A2 (i.e. the mixture of Form 1A and Form 1B described in WO2014138639A1), the Form 1A described in WO2014138639A1, or the Form 1B described in WO2014138639A1, most preferably delafloxacin meglumine described in WO2006042034A2 Methylamine salt anhydrate crystal form;

Further, according to the preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the alcohol solvent is preferably one or both of methanol and ethanol, more preferably methanol or ethanol, most preferably methanol;

Further, according to the preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the esters/ketones/ethers/alkanes are preferably one or more of acetone, ethyl acetate, diethyl ether, isopropyl ether methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methylcyclohexane, more preferably acetone, ethyl acetate, diethyl ether, isopropyl ether methyl tert-butyl ether, One of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methylcyclohexane, most preferably acetone;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the volume ratio of alcohols to esters/ketones/ethers/alkanes in the mixed solvent of alcohols and esters/ketones/ethers/alkanes can be 0.5:1~1:0.5, preferably 4:5~1:1, most preferably 4:5;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the temperature during the stirring can be 40-70°C, preferably 50-64°C, most preferably 64°C;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the stirring time is until it dissolves, more preferably 0.5 to 1 hour, most preferably 1 hour;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the concentration of the solution obtained after the stirring can be 10 mg/mL-30 mg/mL, preferably 22 mg/mL-30 mg/mL, most preferably 22 mg/mL;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that after the membrane filtration and before solid precipitation, it may further include static filtration; the static filtration is preferably performed at 5°C;

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the temperature of the drying material is 30-100°C, preferably 50-70°C, most preferably 70°C;

Further, according to the preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the drying time is 12 to 24 hours, preferably 12 to 20 hours, more preferably 14 to 1 hours, more preferably 15 to 17 hours, most preferably 16 hours;

Further, according to the preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that it comprises the following steps:

Take the crude product of delafloxacin meglumine salt and add it to a mixed solvent of methanol and acetone with a volume ratio of 0.5:1 to 1:0.5 to dissolve it into a solution with a concentration of 10 mg/mL to 30 mg/mL, stir at 40 to 70°C, filter through a membrane, solids are precipitated, filter with suction, and dry the material to obtain the product;

Preferably, the preparation method of the new crystal form of delafloxacin meglumine salt comprises the following steps:

Take the crude product of delafloxacin meglumine salt, add a mixed solvent of methanol and acetone with a volume ratio of 4:5 to 1:1, dissolve it into a solution with a concentration of 10 mg/mL to 30 mg/mL, stir at 40 to 70 ° C, filter through a membrane, solids are precipitated, filter with suction, and dry the material to obtain the product;

More preferably, the preparation method of the new crystal form of delafloxacin meglumine salt comprises the following steps:

Take the crude product of delafloxacin meglumine salt and add it into a mixed solvent of methanol and acetone with a volume ratio of 4:5 to 1:1 to dissolve it into a solution with a concentration of 22 mg/mL to 30 mg/mL, stir at 40 to 70 ° C, and filter through a membrane. Solids are precipitated, filtered with suction, and dried to obtain the product;

Especially preferably, the preparation method of the new crystal form of delafloxacin meglumine salt comprises the following steps:

Take the crude product of delafloxacin meglumine salt, add methanol and acetone mixed solvent with a volume ratio of 4:5 to 1:1, dissolve it into a solution with a concentration of 22 mg/mL to 30 mg/mL, stir at 50 to 64 °C, filter with a membrane, solids are precipitated, filter with suction, and dry at 50 to 70 °C to obtain the product;

Most preferably, the preparation method of the new crystal form of delafloxacin meglumine salt comprises the following steps:

Take the crude product of delafloxacin meglumine salt and add a mixed solvent of methanol and acetone with a volume ratio of 4:5 to dissolve it into a solution with a concentration of 22mg/mL, stir at 64°C for 1 hour, filter through a membrane, solids are precipitated, filter with suction, and bake at 70°C for 16 hours to obtain the product.

Further, according to the above-mentioned preparation method of the new crystal form of delafloxacin meglumine salt, it is characterized in that the crude product of delafloxacin meglumine salt can be delafloxacin meglumine salt amorphous form or delafloxacin meglumine salt crystal form, preferably delafloxacin meglumine salt anhydrate crystal form or delafloxacin meglumine salt trihydrate crystal form, more preferably delafloxacin meglumine salt anhydrate crystal form, more preferably WO200604 The delafloxacin meglumine salt anhydrate crystal form described in 2034A2 (i.e. the mixture of Form 1A and Form 1B described in WO2014138639A1), the Form 1A described in WO2014138639A1, or the Form 1B described in WO2014138639A1, most preferably delafloxacin meglumine described in WO2006042034A2 Amine salt anhydrate crystal form;

The "stirring" can be accomplished by conventional methods in this field, such as magnetic stirring, mechanical stirring, etc., and the stirring speed is 50-1800 rpm, preferably 300-900 rpm;

The "anhydrous matter" means that the sample contains no more than 1.5% (weight ratio) or no more than 1.0% (weight ratio) of water detected by TGA;

In the present invention, "crystal" or "crystal form" refers to what is characterized by the shown X-ray diffraction pattern. Those skilled in the art will appreciate that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is well known to those skilled in the art that X-ray diffraction patterns often vary with the conditions of the instrument. In particular, it should be pointed out that the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and the error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as the height of the sample, the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, those skilled in the art can understand that any crystal form having the same or similar characteristic peaks as the spectrum of the present invention falls within the scope of the present invention.

The "crystal" or "crystal form" mentioned in the present invention is pure and single, basically without mixing any other crystal forms. In the present invention, when "substantially free" is used to refer to a new crystal form, it means that this crystal form contains not less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, even less than 5% (weight) of other crystal forms, and even less than 1% (weight) of other crystal forms.

"Pharmaceutically acceptable" in the present invention refers to those compounds, raw materials, compositions and/or dosage forms that are suitable for use in contact with tissues of humans and animals within the scope of sound medical judgment, and without excessive toxicity, irritation, allergic reactions, and other problems and complications, which conform to a reasonable benefit/risk ratio.

"Crystalline" in the present invention means molecules or outer surface planes that are neatly and repeatedly arranged.

The term "amorphous" in the present invention means that molecules or outer surface planes substantially do not regularly repeat.

The "mixture" in the present invention means a combination of at least two substances, one of which can be completely dissolved, partially dissolved or substantially insoluble in the other substance.

The "solvent" in the present invention means a substance, preferably a liquid or a miscible, partially miscible or immiscible mixture of two or more liquids, which can completely dissolve, partially dissolve, disperse or partially disperse another substance, preferably a solid or a mixture of solids.

The "anti-solvent" in the present invention means a solvent in which a compound is substantially insoluble.

The third aspect of the present invention provides a tablet, which contains a therapeutically and/or preventively effective amount of pharmaceutical active ingredients selected from the new crystal form of delafloxacin meglumine salt of the present invention or the new crystal form of delafloxacin meglumine salt of the present invention obtained according to the preparation method of the present invention, and at least one pharmaceutically acceptable carrier or auxiliary agent. The tablet may also contain other pharmaceutically acceptable crystal forms or amorphous substances of delafloxacin meglumine salt or crystal forms or amorphous substances of other pharmaceutically acceptable salts of delafloxacin. Optionally, the tablet contains one or more other pharmaceutically active ingredients, including but not limited to other antimicrobials.

Further, according to the above tablet, it is characterized in that the pharmaceutically acceptable carrier or auxiliary agent includes but is not limited to: diluents, such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; Sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, etc.; lubricants, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; complex formers, such as various grades of cyclodextrins and resins; release rate control agents, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, waxes, etc. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film-forming agents, plasticizers, coloring agents, flavoring agents, viscosity regulators, preservatives, antioxidants, and the like. Each carrier or adjuvant must be acceptable, compatible with the other ingredients in the formulation and not harmful to the patient.

Further, according to the above tablet, it is characterized in that the formulation of the tablet can be suitable for quick release, delayed release or regulated release of the active ingredient.

Further, according to the above tablet, it is characterized in that the tablet can be prepared by methods known to those skilled in the art. When preparing the tablet, the new crystal form of delafloxacin meglumine salt of the present invention is mixed with one or more pharmaceutically acceptable carriers or adjuvants, optionally, with one or more other active pharmaceutical ingredients. Preferably, the tablet can be prepared by mixing, granulating and other processes.

The fourth aspect of the present invention provides a use of the above-mentioned new crystal form of delafloxacin meglumine salt or the new crystal form of delafloxacin meglumine salt prepared by the above method in the preparation of a medicament for treating and/or preventing bacterial infection; the bacterial infection is preferably acute bacterial skin and skin structure infection, or community-acquired bacterial pneumonia infection. The medicament for treating and/or preventing bacterial infection is preferably the aforementioned tablet containing the new crystal form of delafloxacin meglumine salt of the present invention. Different doses are used according to the method of administration, the patient's age, body weight and condition. Typically in the case of oral administration, about 450 mg of the tablet is given per adult every 12 hours.

The new crystal form of delafloxacin meglumine salt provided by the present invention and its preparation method have the beneficial effects of:

1. The TGA diagrams of Figure 9 and Figure 11 provided by the present invention show that the new crystal form of delafloxacin meglumine salt provided by the present invention is an anhydrous crystal form, which is suitable for tablet application and industrialization;

2. The XRPD pattern of Figure 8 provided by the present invention shows that the new crystal form of delafloxacin meglumine salt provided by the present invention has high crystallinity;

3. In Example 4 provided by the present invention, on the basis of Example 1, the crystal form obtained by enlarging all the starting materials by about 20 times remains unchanged, which reflects that the new crystal form of delafloxacin meglumine salt and its preparation method provided by the present invention have good amplification effect, good production reproducibility, good preparation stability, simple operation, suitable for production on a commercial scale, and suitable for industrialization;

4. The thermal stability of the new crystal form of delafloxacin meglumine salt provided by the present invention is good: the DSC charts in Figure 10 and Figure 12 show that the crystal form has no crystal transformation peak between 0 and 232°C, that is, the crystal form is thermally stable below 232°C;

5. Example 5 provided by the present invention shows that the new crystalline form of delafloxacin meglumine salt provided by the present invention has low residual solvent, high chemical purity, is suitable for use in tablets, and is suitable for industrialization;

6. Through the stability competition experiment of crystal slurry in the mixed solvent system of methanol and acetone in the stability test 1, the known delafloxacin meglumine salt anhydrous crystal form is transformed into the new crystal form of delafloxacin meglumine salt of the present invention, the known delafloxacin meglumine salt Form 1A is transformed into the new crystal form of delafloxacin meglumine salt of the present invention, and the known delafloxacin meglumine salt Form 1B is transformed into the new crystal form of delafloxacin meglumine salt of the present invention, and the delafloxacin meglumine salt of the present invention is transformed into the new crystal form of the present invention. The new crystal form of delafloxacin meglumine salt remains unchanged, indicating that the new crystal form of delafloxacin meglumine salt of the present invention is more stable than the known anhydrous crystal form of delafloxacin meglumine salt, known delafloxacin meglumine salt Form 1A and known delafloxacin meglumine salt Form 1B;

7. In the comparative test, the new crystal form of delafloxacin meglumine salt provided by the present invention was heated and stirred in methanol, acetone, and a mixed solvent of methanol and acetone, respectively, and then lowered to room temperature and stirred overnight. The results showed that the new crystal form of delafloxacin meglumine salt provided by the present invention was difficult to dissolve in methanol and acetone, but dissolved in a mixed solvent of methanol and acetone;

8. In Stability Test 2, the new crystal form of delafloxacin meglumine salt provided by the present invention was stored under the condition of 40°C/75%RH for 3 and 6 months respectively, and the crystal form and melting point remained unchanged after being stored unsealed under the condition of 40°C/75%RH for 1 and 3 months.

The above -mentioned beneficial effects of the new crystal type of the pupa saladsine salt and its preparation methods provided by the present invention show that compared with the known crystal type, the crystal type provided by the present invention has good preparation stability and storage stability, which can adapt to the environmental conditions of more loose manufacturing, storage and transportation. Drug activity ingredients are unevenly and decreased in purity, which reduces the risk and safety risk of curative effects brought about by it. It is more suitable for application of tablets, more suitable for industrialization, and high industrial applications and economic value.

Description of drawings

Fig. 1 is the XRPD pattern of the known delafloxacin meglumine salt anhydrate crystal form prepared in comparative example 1 of the present invention;

Fig. 2 is the TGA figure of the known delafloxacin meglumine salt anhydrate crystal form prepared in comparative example 1 of the present invention;

Fig. 3 is the DSC figure of the known delafloxacin meglumine salt anhydrate crystal form prepared in comparative example 1 of the present invention;

Fig. 4 is the XRPD pattern of the known delafloxacin meglumine salt trihydrate crystal form prepared in comparative example 2 of the present invention;

Fig. 5 is the TGA diagram of the known delafloxacin meglumine salt trihydrate crystal form prepared in comparative example 2 of the present invention;

Fig. 6 is the DSC diagram of the known delafloxacin meglumine salt trihydrate crystal form prepared in comparative example 2 of the present invention;

Fig. 7 is the HPLC figure of the new crystal form of delafloxacin meglumine salt prepared in Example 1 of the present invention;

Fig. 8 is the XRPD pattern of the new crystal form of delafloxacin meglumine salt prepared in Example 1 of the present invention;

Fig. 9 is the TGA figure of the new crystal form of delafloxacin meglumine salt prepared in Example 1 of the present invention;

Figure 10 is the DSC figure of the new crystal form of delafloxacin meglumine salt prepared in Example 1 of the present invention;

Fig. 11 is the TGA figure of the new crystal form of delafloxacin meglumine salt prepared in Example 4 of the present invention;

Figure 12 is the DSC figure of the new crystal form of delafloxacin meglumine salt prepared in Example 4 of the present invention;

Figure 13 is the XRPD pattern of the crystal form mixture obtained after 7-day stability competition of the new crystal form of delafloxacin meglumine salt and the known Form 1A, Form 1B, delafloxacin meglumine salt anhydrate crystal form of stability test 1 of the present invention.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the embodiments and accompanying drawings. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.

Instruments and methods used to collect data:

X-ray powder diffraction (XPRD): The instrument used is Bruker D8 Advance diffractometer, using Ka X-ray with a copper target wavelength of 1.54nm, under the operating conditions of 40kV and 180mA, θ-2θ goniometer, Mo monochromator, Lynxeye detector. The instrument is calibrated with the standard product (usually corundum) that comes with the instrument before use. Samples are tested at room temperature, and the sample to be tested is placed on a non-reflective plate. The detailed detection conditions are as follows, angle range: 3-50°2θ, step size: 0.02°2θ, speed: 0.12 seconds/step.

The differential thermal analysis (DSC) data was collected from METTLER TOLEDO DSC3, the instrument control software was STARe Software, and the analysis software was STARe Software Application. Usually 1-10 mg of sample is placed in a standard aluminum pan, and the sample is raised from 0°C to 350°C at a heating rate of 10°C/min under the protection of 50mL/min dry nitrogen.

The thermogravimetric analysis (TGA) data was collected from METTLER TOLEDO TGA2, the instrument control software was STARe Software, and the analysis software was STARe Software Application. Usually 5-15 mg of sample is placed in an aluminum crucible, and the sample is raised from room temperature to 350 °C under the protection of 40 mL/min dry nitrogen at a heating rate of 10 °C/min.

The temperature in the examples is room temperature unless otherwise specified.

In the examples, the ratios of the components in the mixed solvent are volume ratios unless otherwise specified.

Delafloxacin, meglumine, solvents and reagents mentioned in the following examples can all be purchased directly from the market.

Comparative Example 1: Preparation of delafloxacin meglumine salt anhydrate crystal form (preparation method of Example 1 in WO2006042034A2)

Add 50Kg delafloxacin and 21.6Kg meglumine to 75.5Kg water and 60.2Kg isopropanol, dissolve at 45°C, drop to 30±5°C, add 175.7Kg isopropanol and keep warm at 30°C for crystallization. Filter, wash the filter cake with isopropanol and vacuum dry at 30°C for 12 hours, then continue to dry at 50°C to obtain a light yellow solid, which is the crude product of delafloxacin meglumine salt.

Its XRPD pattern is shown in Figure 1, showing a crystalline state;

Its TGA diagram is shown in Figure 2, which shows that there is a period of weight loss of about 0.9% before 100°C, and the weight loss is about 8.5% at 100°C-250°C;

Its DSC chart is shown in Figure 3, showing that the melting point is about 172°C.

Comparative Example 2: Preparation of delafloxacin meglumine salt trihydrate crystal form (preparation method of Example 2 in WO2006042034A2)

Add 29.6Kg delafloxacin and 18.4Kg meglumine to 133Kg water, dissolve at 60°C, lower to 38°C and keep stirring until solid precipitates, then continue to cool down to 0°C for crystallization. After filtering, the filter cake was washed with isopropanol and dried under vacuum at 50°C to obtain a pale yellow solid.

Its XRPD pattern is as shown in Figure 4, showing a crystalline state;

Its TGA diagram is shown in Figure 5, which shows that there is a period of weight loss of about 7.8% before 110°C, and the weight loss is about 7.0% at 110°C-240°C;

Its DSC chart is shown in Figure 6, which shows that there is an endothermic peak before 120°C, and the melting point is about 172°C. Comparative Example 3: Preparation of delafloxacin meglumine salt Form 1A (preparation method of WO2014138639A1)

100Kg of the wet trihydrate prepared in Comparative Example 2 was vacuum-dried at 35°C for 17h, then vacuum-dried at 55°C for 24h, and then wetted with a nitrogen flow of 40%-60%RH at 50-55°C until all the crystals were transformed into Form 1A. After continued wetting for 18h, vacuum-dried at 55°C for 48h.

Comparative Example 4: Preparation of delafloxacin meglumine salt Form 1B (preparation method of WO2014138639A1)

The trihydrate prepared in Comparative Example 2 was dried at 3mbar/30°C for 12h and then transformed into Form 1B.

Embodiment 1: Preparation of new crystal form of delafloxacin meglumine salt

Take 1.5g of the crude delafloxacin meglumine salt prepared in Comparative Example 1, add 50mL of methanol and 50mL of acetone, stir at 50°C to dissolve, membrane filter, stand overnight at 5°C, and solids precipitate out. Filtrate and dry at 50°C to obtain a new crystal form with a purity of 99.965% (see Figure 7 for the HPLC spectrum) and a yield of 56%. Its XRPD pattern is shown in Figure 8;

Its TGA chart is shown in Figure 9, which shows that there is a period of weight loss of about 2.3% before 120°C, and the weight loss is about 1.1% at 120°C-240°C;

Its DSC chart is shown in Figure 10, showing that the melting point is about 230°C.

Embodiment 2: Preparation of new crystal form of delafloxacin meglumine salt

Take 1.0 g of the crude delafloxacin meglumine salt prepared in Comparative Example 1, add 50 mL of methanol and 50 mL of acetone, stir at 60°C for about 1 hour, filter through a membrane, solids are precipitated, keep stirring at 5°C for 0.5 hours, filter with suction, and bake at 70°C for 22 hours to obtain a new crystal form with a yield of 56%.

Embodiment 3: Preparation of new crystal form of delafloxacin meglumine salt

Take 5.0 g of the crude product of delafloxacin meglumine salt prepared in Comparative Example 1, add 125 mL of methanol and 125 mL of acetone, stir at 60 ° C for about 0.5 hours, membrane filter, solids are precipitated, keep stirring at 5 ° C for 0.5 hours, suction filter, and bake at 70 ° C for 16 hours to obtain a new crystal form with a yield of 56%.

Embodiment 4: Scale-up preparation of new crystal form of delafloxacin meglumine salt

Take 20g of the crude delafloxacin meglumine salt prepared in Comparative Example 1, add 420mL of methanol and 470mL of acetone, stir at 64°C for about 1 hour, membrane filter, solids precipitate out, filter with suction, and dry at 70°C for 16 hours to obtain a new crystal form with a purity of 99.147% and a yield of 56%.

Its TGA chart is shown in Figure 11, which shows that there is a period of weight loss of about 2.0% before 130°C;

Its DSC chart is shown in Figure 12, showing that the melting point is about 232°C.

Embodiment 5: Solvent residue detection in the new crystal form of delafloxacin meglumine salt

The crystal form sample prepared in Example 2 was subjected to solvent residual detection.

Gas chromatography (GC) detects delafloxacin solvent residues:

Chromatographic column: Agilent 123-1334 DB-624 30m*0.53mm, 3.0μm. Flow rate: 3.5 mL/min. Column temperature: keep at 40°C for 5 minutes, raise to 120°C at 10°C/min, then rise to 260°C at 20°C/min and keep for 5 minutes. The temperature of the injection port is 230° C.; the detector (FID): a hydrogen flame ionization detector. The detector temperature is 230°C; the headspace vial heating temperature is 95°C; the split ratio is 2/1. The diluent is DMSO. The injection volume was 2 mL.

It is measured that the solvent residue is: methanol 0.011% (<0.3%), acetone 0.053% (<0.5%), detailed test results are shown in Table 1 and Table 2:

The detection result of the solvent residue (methanol) of new crystal form scale-up experiment of table 1

The detection result of the solvent residue (acetone) of new crystal form scale-up experiment of table 2

Embodiment 6: preparation contains the tablet of delafloxacin meglumine salt new crystal form of the present invention

The tablet formulation is as follows:

New crystal form of delafloxacin meglumine salt of the present invention	45g
anhydrous citric acid	0.55g
Crospovidone	10.9g
Magnesium stearate	1g
microcrystalline cellulose	41.7g
povidone	3.4g
sodium bicarbonate	14g
Sodium dihydrogen phosphate monohydrate	0.55g
total	117.1g

The preparation steps of the tablet are as follows:

Weigh 0.55g of anhydrous citric acid, 10.9g of crospovidone, 41.7g of microcrystalline cellulose, 3.4g of povidone, 14g of sodium bicarbonate, 0.55g of sodium dihydrogen phosphate monohydrate, and 45g of the new crystal form of delafloxacin meglumine salt, and mix evenly; then add 1g of magnesium stearate, mix evenly;

Stability test 1

For the new crystal form of delafloxacin meglumine salt of the present invention and the known Form 1A, Form 1B, delafloxacin meglumine salt anhydrate crystal form, the stability competition experiment was compared, and the results are shown in Table 3.

The operation process of the described stability competition experiment is: take the delafloxacin meglumine salt new crystal form prepared by any one of the embodiments 1-4 of the present invention, the known delafloxacin meglumine salt anhydrous crystal form prepared by comparative example 1, the known delafloxacin meglumine salt Form 1A prepared by comparative example 3 and the known delafloxacin meglumine salt Form 1B prepared by comparative example 4 respectively, after mixing, place and add 15mL methanol, after stirring at room temperature for 7 days, mix Carry out XRPD characterization (the measured XRPD pattern is shown in accompanying drawing 13), after analysis, in the obtained XRPD pattern, there are only the characteristic peaks of the new crystal form of delafloxacin meglumine salt of the present invention, and there are no characteristic peaks of the known Form 1A, Form 1B or the anhydrous crystal form of delafloxacin meglumine salt. Therefore, the results of the competition experiments are shown in Table 3.

Table 3 Stability competition test results

From the results in Table 3, it can be seen that: through the stability competition experiment of crystal slurry in a mixed solvent system of methanol and acetone at 40°C, the known delafloxacin meglumine salt anhydrate crystal form is transformed into the new crystal form of delafloxacin meglumine salt of the present invention, the known delafloxacin meglumine salt Form 1A is transformed into the new crystal form of delafloxacin meglumine salt of the present invention, and the known delafloxacin meglumine salt Form 1B is transformed into the new crystal form of delafloxacin meglumine salt of the present invention , while the new crystal form of delafloxacin meglumine salt of the present invention remains unchanged, indicating that the new crystal form of delafloxacin meglumine salt of the present invention is more stable than the known anhydrous crystal form of delafloxacin meglumine salt, known delafloxacin meglumine salt Form 1A and known delafloxacin meglumine salt Form 1B.

Stability test 2

Carry out the stability test of the new crystal form of delafloxacin meglumine salt of the present invention under the following conditions:

Storage conditions 1:

Under the condition of 40℃/75%RH, store in sealed state for 3 and 6 months;

Storage conditions 2:

Under the condition of 40℃/75%RH, store in an unsealed state for 1 and 3 months;

As a result, after 3 months under storage condition 1, and after 1 month under storage condition 2, the crystal form and melting point of the new crystal form of delafloxacin meglumine salt of the present invention were detected by XRPD and DSC; after 6 months under storage condition 1 and after 3 months under storage condition 2, the crystal form and melting point of the new crystal form of delafloxacin meglumine salt of the present invention were further detected by XRPD and DSC;

On the other hand, compared with before the start of the test, the total amount of impurities in the new crystal form of delafloxacin meglumine salt of the present invention did not change during the whole test period.

Comparative Test

Take the crude product of delafloxacin meglumine salt prepared in Comparative Example 1, add the amount of solvent shown in Table 4 below, place it in a constant temperature stirrer, start to heat up to 50°C, keep stirring to observe and record its dissolution.

Table 4

quality	solvent	volume	Phenomenon
3.0g	Methanol	150mL	undissolved serum
2.0g	acetone	120mL	undissolved serum
1.5g	methanol + acetone	50mL+50mL	Solvent

All patent documents and non-patent publications cited in this specification are hereby incorporated by reference in their entirety.

Unless stated otherwise, percentages stated throughout the specification of this application are weight/weight (w/w) percentages. The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (9)

1. A new crystal form of delafloxacin meglumine salt, characterized in that, using Cu-Kɑ radiation, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 7.323±0.2°, 8.079±0.2°, 8.377±0.2°, 9.539±0.2°, 15.139±0.2°, 18.422±0.2°.
2. The new crystal form of delafloxacin meglumine salt according to claim 1 is further characterized in that its X-ray powder diffraction pattern also has one or more diffraction peaks at the following 2θ angles: 8.638±0.2°, 13.621±0.2°, 16.260±0.2°, 17.721±0.2°, 19.121±0.2°, 19.960±0.2°.
3. The new crystal form of delafloxacin meglumine salt according to claim 2 is further characterized in that its X-ray powder diffraction pattern also has one or more diffraction peaks at the following 2θ angles: 21.279±0.2°, 22.140±0.2°, 22.718±0.2°, 23.801±0.2°, 25.820±0.2°, 27.100±0.2°.
4. The new crystal form of delafloxacin meglumine salt according to claim 3 is further characterized in that it has an X-ray powder diffraction pattern substantially the same as that of FIG. 8 .
5. A preparation method of the new crystal form of delafloxacin meglumine salt according to claim 5, characterized in that it comprises the steps of:

   The crude product of delafloxacin meglumine salt is dissolved in a mixed solvent of alcohols and esters/ketones/ethers/alkanes, stirred, membrane filtered, solids are precipitated, filtered, and dried to obtain the product.
6. The preparation method according to claim 6, wherein the crude product of delafloxacin meglumine salt is preferably delafloxacin meglumine salt amorphous form or delafloxacin meglumine salt crystal form, more preferably delafloxacin meglumine salt anhydrous crystal form or delafloxacin meglumine salt trihydrate crystal form, more preferably delafloxacin meglumine salt anhydrate crystal form, especially preferably delafloxacin meglumine salt anhydrous crystal form as recorded in WO2006042034A2 Anhydrous crystal form of star meglumine salt, Form 1A described in WO2014138639A1, or Form 1B recorded in WO2014138639A1, most preferably delafloxacin meglumine salt anhydrate crystal form described in WO2006042034A2;

   And/or, the alcoholic solvent is preferably one or both of methanol and ethanol, more preferably methanol or ethanol, most preferably methanol;

   And/or, the esters/ketones/ethers/alkanes are preferably one or more of acetone, ethyl acetate, ether, isopropyl ether methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methylcyclohexane, more preferably acetone, ethyl acetate, ether, isopropyl ether methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane One of alkane, chloroform, methylcyclohexane, most preferably acetone;

   And/or, the volume ratio of alcohols to esters/ketones/ethers/alkanes in the mixed solvent of alcohols and esters/ketones/ethers/alkanes can be 0.5:1-1:0.5, preferably 4:5-1:1, most preferably 4:5;

   And/or, the temperature during the stirring may be 40-70°C, preferably 50-64°C, most preferably 64°C;

   And/or, the stirring time is until it dissolves, more preferably 0.5-1 hour, most preferably 1 hour;

   And/or, the concentration of the solution obtained after the stirring may be 10 mg/mL-30 mg/mL, preferably 22 mg/mL-30 mg/mL, most preferably 22 mg/mL;

   And/or, after the membrane filtration and before solid precipitation, static filtration may be further included, and the static filtration is preferably performed at 5°C;

   And/or, the temperature of the drying material is 30-100°C, preferably 50-70°C, most preferably 70°C;

   And/or, the drying time is 12-24 hours, preferably 12-20°C, more preferably 14-18°C, more preferably 15-17°C, most preferably 16 hours.
7. A method for preparing a new crystal form of delafloxacin meglumine salt according to claim 5, characterized in that it comprises the following steps: taking the crude product of delafloxacin meglumine salt, adding a mixed solvent of methanol and acetone with a volume ratio of 0.5:1 to 1:0.5, and dissolving it into a solution with a concentration of 10 mg/mL to 30 mg/mL, stirring at 40 to 70 ° C, membrane filtration, solid precipitation, suction filtration, and drying.
8. A tablet, characterized in that it comprises the new crystal form of delafloxacin meglumine salt according to claim 5 or the new crystal form of delafloxacin meglumine salt of the present invention obtained by the preparation method described in any one of claims 6 to 8, and at least one pharmaceutically acceptable carrier or auxiliary agent.
9. Use of the new crystal form of delafloxacin meglumine salt according to claim 5 or the new crystal form of delafloxacin meglumine salt of the present invention obtained by the preparation method described in any one of claims 6 to 8 in the preparation of medicines for treating and/or preventing bacterial infections.

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