CN116514775A

CN116514775A - New crystal form of meglumine salt of DELASHANXIA and preparation method thereof

Info

Publication number: CN116514775A
Application number: CN202210066268.XA
Authority: CN
Inventors: 朱逸凡; 范敏华; 李凯; 梁贝贝; 周胜军
Original assignee: Anhui Puli Pharmaceutical Co ltd; Zhejiang Poly Pharmaceutical Co ltd; Hainan Poly Pharm Co ltd
Current assignee: Anhui Puli Pharmaceutical Co ltd
Priority date: 2022-01-20
Filing date: 2022-01-20
Publication date: 2023-08-01
Also published as: WO2023137966A1

Abstract

The invention provides a novel crystal form of a Grafloxacin meglumine salt and a preparation method thereof, wherein an X-ray powder diffraction pattern of the novel crystal form has diffraction peaks at the following 2 theta angles: 7.323 +/-0.2 degrees, 8.079 +/-0.2 degrees, 8.377 +/-0.2 degrees, 9.539 +/-0.2 degrees, 15.139 +/-0.2 degrees and 18.422 +/-0.2 degrees, and the preparation method comprises the following steps: dissolving crude product of Grafloxacin meglumine salt in mixed solvent of alcohols and esters/ketones/ethers/alkanes, stirring, membrane filtering to obtain solid, filtering, and oven drying. The novel crystal form of the Grafloxacin meglumine salt provided by the invention has good preparation stability and storage stability, can be suitable for more relaxed manufacturing, storage and transportation environment conditions, can better resist the problems of uneven active ingredients, reduced purity and the like of medicaments possibly caused by factors such as temperature, humidity, crystal form change and the like, reduces the risk of reduced curative effect and safety risk caused by the uneven active ingredients, is more suitable for tablets, is more suitable for industrialization, and has high industrial application and economic value.

Description

New crystal form of meglumine salt of DELASHANXIA and preparation method thereof

Technical Field

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

Background

After norfloxacin was found since the end of the 70 th century, fluoroquinolones developed rapidly, and a large number of products have been marketed.

Deraxacin (English name: delafloxacin), a fluoroquinolone compound with a brand new structure developed by Yongyong pharmaceutical company of Japan, has a chemical name of 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, and has a chemical structure shown in the following formula I:

the chemical structure of the meglumine salt is shown as the following formula II:

delafloxacin (english name: delafloxacin) is a new generation of broad-spectrum fluoroquinolone antibacterial agent, has excellent broad-spectrum antibacterial activity and bactericidal activity, has an action target of bacterial DNA topoisomerase, is more effective against gram-positive bacteria than other quinolone antibacterial agents, and particularly has a methicillin-resistant staphylococcus aureus resistant to other quinolone antibacterial agents, and clinically shows that the Delafloxacin can be applied to the treatment of community-acquired pneumonia and skin soft tissue infection, and the treatment of respiratory tract and urinary system infection. Currently approved by the FDA in the united states under the trade name Baxdela for the treatment of bacterial skin and skin structure infections, the marketed dosage form includes tablets, which are marketed as delafloxacin meglumine salt. Therefore, the research on the crystal form of the delafloxacin meglumine salt has very important significance for the development of tablets.

PCT application WO2006042034A2 discloses delafloxacin meglumine salt anhydrate and delafloxacin meglumine salt trihydrate forms and methods for their preparation and characterization with XRPD, but applicant found that the delafloxacin meglumine salt anhydrate and delafloxacin meglumine salt trihydrate forms disclosed in WO2006042034A2 suffer from the following drawbacks:

1. since the delafloxacin meglumine salt anhydrate crystal form and the delafloxacin meglumine salt trihydrate crystal form disclosed in PCT application WO2006042034A2 and the preparation method thereof are the delafloxacin meglumine salt anhydrate crystal form and the delafloxacin meglumine salt trihydrate crystal form prepared from the same solvent system, the products are mostly in the mixed form of the delafloxacin meglumine salt anhydrate crystal form and the delafloxacin meglumine salt trihydrate crystal form, so that the delafloxacin meglumine salt anhydrate crystal form and the delafloxacin meglumine salt trihydrate crystal form have poor process preparation repeatability and poor preparation stability, and are not suitable for industrial production;

2. the delafloxacin meglumine salt anhydrous crystal form is easy to absorb moisture and can be converted into a trihydrate crystal form in a high-humidity environment, so that the storage stability is poor, and the tablet prepared from the delafloxacin meglumine salt anhydrous crystal form can have the problems of unstable storage, unstable active ingredient content, increased impurity content in the storage process, poor production reproducibility, reduced drug effect, poor product quality stability and the like;

3. the DSC profile of comparative example 2 of the present application shows that the trihydrate crystalline form is thermally unstable, and at 120 ℃ seeding occurs, converting to the anhydrate crystalline form.

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

1. european drug specifications for delafloxacin meglumine salt disclose Form 1A as a variable hemihydrate, which converts to a trihydrate in a high humidity environment, and has poor stability; form 1B is a metastable crystalline Form that converts Form 1B to Form 1A when exposed to a particular humidity and high temperature; the tablet prepared from Form 1A and Form 1B may have the problems of unstable storage, poor production reproducibility, unstable active ingredient content, increased impurity content during storage, reduced drug effect, poor product quality stability and the like;

form 1b is obtained by drying and crystal transformation of a trihydrate crystal form under a low humidity condition, has harsh preparation conditions and large process improvement difficulty, and is not suitable for industrial scale production;

form 1a is obtained by drying a trihydrate crystal form under vacuum, then exposing the dried form to high temperature and humidity, and carrying out crystal transformation, and the preparation conditions are harsh, the process improvement difficulty is high, and the method is not suitable for industrial scale production.

In summary, the existing delafloxacin meglumine salt crystal forms are not suitable for industrial scale production, nor are they suitable for use as active ingredients in tablets for preparing tablets meeting registration standards, and therefore, it is necessary to develop new delafloxacin meglumine salt crystal forms that have high crystallinity, good bioavailability, good stability, good production reproducibility, good amplification effect, low hygroscopicity, good compressibility, low residual solvents, high chemical purity, suitability for use in tablets, and industrialization feasibility, so as to solve the problems associated with the prior art and make them suitable for mass production and tablets.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to solve the problems of the existing delafloxacin meglumine salt crystal form by providing a novel delafloxacin meglumine salt crystal form and a preparation method thereof. Meanwhile, the invention also relates to a preparation method of the novel crystal form, and a pharmaceutical composition and application thereof.

The new crystalline form has at least one of the following advantageous properties compared to existing delafloxacin meglumine salt crystalline forms: good stability, such as crystal form stability, thermal stability, chemical stability, mechanical stability, storage stability, etc.; the solubility is good; the dissolution speed is high; the bioavailability is good; the crystallinity is high; the production reproducibility is good; the amplification effect is good; not easy to absorb moisture; easy purification and treatment; the chemical purity is high; low residual solvent; the particle shape is good; suitable formulations are processible, for example, good flowability, advantageous powder viscosity, compactibility and compressibility, good appearance; improving bioavailability and drug effect of the preparation; prolonging the shelf life of the preparation; is suitable for new dosage form application.

The technical scheme of the invention is as follows:

the invention provides a novel crystal form of a meglumine salt of delafloxacin, which is characterized in that Cu-K alpha radiation is used, and an X-ray powder diffraction pattern of the novel crystal form has diffraction peaks at the following 2 theta 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, the novel crystal form of the meglumine salt of the delafloxacin is characterized in that the X-ray powder diffraction pattern of the novel crystal form of the meglumine salt of the delafloxacin also has one or more diffraction peaks at the following 2 theta 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 novel crystalline form of the 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 °, 17.721 + -0.2 °;

more preferably, the novel crystalline form of the 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 °, 17.721 + -0.2 °, 18.422 + -0.2 °, 19.121 + -0.2 °, 19.960 + -0.2 °;

further, the novel crystal form of the meglumine salt of the delafloxacin is characterized in that the X-ray powder diffraction pattern of the novel crystal form of the meglumine salt of the delafloxacin also has one or more diffraction peaks at the following 2 theta 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 novel crystalline form of the 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 °, 17.721 + -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 novel crystalline form of the 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 °, 17.721 + -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 novel crystalline form of the delafloxacin meglumine salt has diffraction peaks at the following 2θ angles:

in a particularly preferred embodiment of the present invention, the present invention provides a novel crystalline form of the meglumine salt of delafloxacin having an X-ray powder diffraction pattern substantially the same as figure 8;

in an embodiment of the present invention, the novel crystalline form of the meglumine salt of delafloxacin provided herein is substantially anhydrous, having a solvent residue of less than 2.3 wt%, preferably less than 2.0 wt%, and a TGA profile as shown in fig. 9 or 11;

in an embodiment of the present invention, the novel crystalline form of the meglumine salt of delafloxacin provided by the present invention has a melting point of about 230 to 232 ℃, preferably about 230 ℃ or 232 ℃, and a DSC diagram thereof is shown in fig. 10 or 12;

in a second aspect, the invention provides a preparation method of a novel crystal form of a meglumine salt of DELAXionsand, which comprises the following steps:

dissolving crude meglumine salt of DELAXfloxacin in mixed solvent of alcohols and esters/ketones/ethers/alkanes, stirring, membrane filtering to obtain solid, filtering, and oven drying to obtain the final product;

further, according to the above method for preparing a new crystalline Form of delafloxacin meglumine salt, the crude delafloxacin meglumine salt may be amorphous Form of delafloxacin meglumine salt or Form 1B of delafloxacin meglumine salt, preferably Form anhydrous Form of delafloxacin meglumine salt or Form trihydrate, more preferably Form anhydrous Form of delafloxacin meglumine salt described in WO2006042034A2 (i.e. mixture of Form 1A and Form 1B described in WO2014138639 A1), form 1A described in WO2014138639A1, or Form 1B described in WO2014138639A1, most preferably Form anhydrous Form of delafloxacin meglumine salt described in WO2006042034 A2;

further, according to the preparation method of the novel crystal form of the delafloxacin meglumine salt, the preparation method is characterized in that the alcohol solvent is preferably one or two of methanol and ethanol, more preferably methanol or ethanol, and most preferably methanol;

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

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

further, according to the preparation method of the novel crystal form of the delafloxacin meglumine salt, the temperature during stirring can be 40-70 ℃, preferably 50-64 ℃ and most preferably 64 ℃;

further, according to the above process for preparing the novel crystalline form of the meglumine salt of delafloxacin, the stirring time is from stirring to dissolving, more preferably 0.5 to 1 hour, most preferably 1 hour;

further, according to the preparation method of the novel crystal form of the meglumine salt of the delafloxacin, the concentration of the solution obtained after stirring can be 10mg/mL to 30mg/mL, preferably 22mg/mL to 30mg/mL, and most preferably 22mg/mL;

further, the preparation method of the novel crystal form of the delafloxacin meglumine salt is characterized in that the membrane filtration and the still standing filtration can be further included before the solid precipitation; the stationary filtration is preferably carried out at 5 ℃;

further, according to the preparation method of the novel crystal form of the delafloxacin meglumine salt, the preparation method is characterized in that the temperature during material drying is 30-100 ℃, preferably 50-70 ℃ and most preferably 70 ℃;

further, according to the above process for preparing the novel crystalline form of the meglumine salt of delafloxacin, the time for baking the material is 12 to 24 hours, preferably 12 to 20 hours, more preferably 14 to 1 hour, still more preferably 15 to 17 hours, most preferably 16 hours;

further, the preparation method of the novel crystal form of the delafloxacin meglumine salt is characterized by comprising the following steps of:

adding a mixed solvent of methanol and acetone with the volume ratio of 0.5:1-1:0.5 into a crude product of the meglumine salt of the DE-LASHUAXUE to dissolve into a solution with the concentration of 10 mg/mL-30 mg/mL, stirring at the temperature of 40-70 ℃, membrane filtering, separating out solids, pumping filtering and drying to obtain the final product;

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

adding a mixed solvent of methanol and acetone with the volume ratio of 4:5-1:1 into a crude product of the meglumine salt of the DE-LASHUAXUE to dissolve into a solution with the concentration of 10 mg/mL-30 mg/mL, stirring at the temperature of 40-70 ℃, membrane filtering, separating out solids, carrying out suction filtration, and drying to obtain the final product;

more preferably, the preparation method of the novel crystal form of the delafloxacin meglumine salt comprises the following steps:

adding a mixed solvent of methanol and acetone with the volume ratio of 4:5-1:1 into a crude product of the meglumine salt of the DE-LASHUAXUE to dissolve into a solution with the concentration of 22-30 mg/mL, stirring at the temperature of 40-70 ℃, membrane filtering, separating out solids, carrying out suction filtration, and drying to obtain the final product;

particularly preferred, the preparation method of the novel crystal form of the delafloxacin meglumine salt comprises the following steps:

adding a mixed solvent of methanol and acetone with the volume ratio of 4:5-1:1 into a crude product of the meglumine salt of the DE-LASHAXIANGHUASHUASHUANMIAN to dissolve into a solution with the concentration of 22 mg/mL-30 mg/mL, stirring at 50-64 ℃, membrane filtering, separating out solids, carrying out suction filtration, and drying at 50-70 ℃ to obtain the final product;

most preferably, the preparation method of the novel crystal form of the delafloxacin meglumine salt comprises the following steps:

adding mixed solvent of methanol and acetone with volume ratio of 4:5 into crude product of meglumine salt of DE-Laxacin, dissolving into solution with concentration of 22mg/mL, stirring at 64deg.C for 1 hr, membrane filtering, separating out solid, suction filtering, and oven drying at 70deg.C for 16 hr.

the "stirring" may be performed by a conventional method in the art, and the stirring manner is, for example, magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm;

by "anhydrate" is meant that the sample contains no more than 1.5 weight percent or no more than 1.0 weight percent water as measured by TGA;

in the present invention, "crystal" or "crystalline form" refers to those that are confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will appreciate that experimental errors therein depend on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns generally vary with the conditions of the instrument. It is particularly pointed out that the relative intensities of the X-ray diffraction patterns may also vary with the experimental conditions, so the order of peak intensities cannot be the only or decisive factor. In addition, experimental errors in peak angles are typically 5% or less, and errors in these angles should also be taken into account, typically allowing for errors of + -0.2 deg.. In addition, due to the influence of experimental factors such as the sample height, an overall shift in peak angle is caused, and generally a certain shift is allowed. Thus, it will be appreciated by those skilled in the art that any crystalline form having the same or similar characteristic peaks as the patterns of the present invention falls within the scope of the present invention.

The "crystals" or "crystalline forms" described herein are pure, single, and essentially free of any other crystalline forms. In the present invention, "substantially free" when used in reference to a new crystalline form means that the crystalline form contains not less than 20% by weight of other crystalline forms, particularly less than 10% by weight of other crystalline forms, more particularly less than 5% by weight of other crystalline forms, and even more particularly less than 1% by weight of other crystalline forms.

By "pharmaceutically acceptable" is meant those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "crystal" as used herein means a molecule or an outer surface plane which is aligned repeatedly.

By "amorphous" as used herein, it is meant that there is substantially no orderly repeated alignment of molecules or planes of the outer surface.

By "mixture" as used herein is meant a combination of at least two substances, one of which may be completely dissolved, partially dissolved or substantially insoluble in the other.

"solvent" as used herein means a substance, preferably a liquid or a mixture of two or more liquids that are miscible, partially miscible or immiscible, that is capable of completely dissolving, partially dissolving, dispersing or partially dispersing another substance, preferably a solid or a mixture of solids.

By "antisolvent" in the context of the present invention is meant a solvent in which the compound is substantially insoluble.

In a third aspect the present invention provides a tablet comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the novel crystalline form of delafloxacin meglumine salt of the invention or the novel crystalline form of delafloxacin meglumine salt of the invention obtained according to the process of the invention, together with at least one pharmaceutically acceptable carrier or adjuvant. The tablet may also comprise other pharmaceutically acceptable crystalline or amorphous forms of delafloxacin meglumine salt or other pharmaceutically acceptable salts of delafloxacin or amorphous forms thereof. Optionally, the tablet comprises one or more other pharmaceutically active ingredients, including but not limited to other antibacterial agents.

Further, the above tablet is characterized in that the pharmaceutically acceptable carrier or adjuvant includes, but is not limited to: diluents such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous dibasic calcium phosphate, tribasic calcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, and the like; disintegrants such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, and the like; complex forming agents, such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl methacrylate, waxes, and the like. Other useful pharmaceutically acceptable carriers include, but are not limited to, film forming agents, plasticizers, colorants, flavoring agents, viscosity modifying agents, preservatives, antioxidants, and the like. Each carrier or adjuvant must be acceptable, compatible with the other ingredients of the formulation, and not deleterious to the patient.

Further, the tablet according to the above, characterized in that the formulation of the tablet may be adapted for a fast, delayed or modified release of the active ingredient.

Further, the tablet according to the above, characterized in that the tablet can be prepared using methods well known to those skilled in the art. In preparing the tablets, the novel crystalline form of the present invention of the meglumine salt of delafloxacin is admixed with one or more pharmaceutically acceptable carriers or adjuvants, optionally with one or more other pharmaceutically active ingredients. Preferably, the tablets may be prepared by mixing, granulating, etc. processes.

The fourth aspect of the invention provides a novel crystal form of the delafloxacin meglumine salt or the novel crystal form of the delafloxacin meglumine salt prepared by the method, and the application of the novel crystal form of the delafloxacin meglumine salt in preparing medicines for treating and/or preventing bacterial infection; the bacterial infection is preferably an acute bacterial skin and skin structure infection, or a community-acquired bacterial pneumonia infection. The medicament for the treatment and/or prophylaxis of bacterial infections is preferably the aforementioned tablet containing the novel crystalline form of the meglumine salt of delafloxacin of the invention. Different dosages are used depending on the administration method, age, weight and condition of the patient. Typically, in the case of oral administration, about 450mg of tablets are administered every 12 hours per adult.

The novel crystal form of the DE-Laxacin meglumine salt and the preparation method thereof provided by the invention have the beneficial effects that:

1. the TGA diagrams of figures 9 and 11 provided by the invention show that the novel crystal form of the meglumine salt of the delafloxacin provided by the invention is an anhydrous crystal form, is suitable for being applied to tablets and is suitable for industrialization;

2. the XRPD pattern of the figure 8 provided by the invention shows that the novel crystal form of the meglumine salt of the delafloxacin provided by the invention has high crystallinity;

3. the crystal form obtained by amplifying all starting materials by about 20 times on the basis of the embodiment 1 is unchanged, so that the amplification effect of the novel crystal form of the delafloxacin meglumine salt and the preparation method thereof provided by the invention is good, the production reproducibility is good, the preparation stability is good, the operation is simple, the preparation method is suitable for commercial scale production, and the method is suitable for industrialization;

4. the novel crystal form of the meglumine salt of the delafloxacin provided by the invention has good thermal stability: the DSC diagrams of FIGS. 10 and 12 show that the crystal form has no crystal transformation peak between 0 and 232 ℃, i.e. the crystal form is thermally stable below 232 ℃;

5. example 5 provided by the invention shows that the novel crystal form of the meglumine salt of the delafloxacin provided by the invention has low residual solvent, high chemical purity, suitability for being applied to tablets and suitability for industrialization;

6. through stability competition experiments in a mixed solvent system of methanol and acetone in the stability test 1, the known delafloxacin meglumine salt anhydrous crystal Form is converted into the novel delafloxacin meglumine salt crystal Form, the known delafloxacin meglumine salt Form 1A is converted into the novel delafloxacin meglumine salt crystal Form, the known delafloxacin meglumine salt Form 1B is converted into the novel delafloxacin meglumine salt crystal Form, and the novel delafloxacin meglumine salt crystal Form of the invention keeps unchanged, so that the novel delafloxacin meglumine salt crystal Form of the invention is more stable than the novel delafloxacin meglumine salt anhydrous crystal Form, the known delafloxacin meglumine salt Form 1A and the known delafloxacin meglumine salt Form 1B.

7. In a comparative experiment, the novel crystal forms of the meglumine salt of the delafloxacin provided by the invention are respectively heated and stirred in methanol, acetone and a mixed solvent of the methanol and the acetone, then cooled to room temperature and stirred overnight, and the result shows that the novel crystal forms of the meglumine salt of the delafloxacin provided by the invention are difficult to dissolve in the methanol and the acetone, but are dissolved in the mixed solvent of the methanol and the acetone;

8. in stability test 2, the novel crystal forms of the meglumine salt of the delafloxacin provided by the invention are respectively stored for 3 and 6 months in a sealed mode under the condition of 40 ℃/75% RH, and the crystal forms and the melting points are unchanged after the novel crystal forms are stored for 1 and 3 months in an unsealed mode under the condition of 40 ℃/75% RH.

The novel crystal form of the DE-Laxacin meglumine salt and the preparation method thereof provided by the invention have the beneficial effects that: compared with the known crystal forms, the crystal forms provided by the invention have good preparation stability and storage stability, can adapt to more relaxed manufacturing, storage and transportation environment conditions, can better resist the problems of uneven active ingredients, reduced purity and the like of medicaments possibly generated by factors such as temperature, humidity, crystal form change and the like, reduce the risks of curative effect reduction and safety risks caused by the uneven active ingredients, are more suitable for tablets, are more suitable for industrialization, and have high industrial application and economic value.

Drawings

FIG. 1 is an XRPD pattern for a crystalline form of the known delafloxacin meglumine salt anhydrate prepared in comparative example 1 of the present invention;

FIG. 2 is a TGA diagram of a crystalline form of the known delafloxacin meglumine salt anhydrate prepared in comparative example 1 of the present invention;

FIG. 3 is a DSC of an anhydrate form of the known meglumine salt of delafloxacin prepared in comparative example 1 of the present invention;

FIG. 4 is an XRPD pattern for a crystalline form of the known delafloxacin meglumine salt trihydrate prepared in comparative example 2 of the invention;

FIG. 5 is a TGA plot of a crystalline form of a salt of delafloxacin meglumine in the known form of comparative example 2 of the present invention;

FIG. 6 is a DSC of a crystalline form of the salt of delafloxacin meglumine in the form of a salt of a trihydrate prepared in comparative example 2 of the present invention;

FIG. 7 is an HPLC chart of novel crystal forms of the meglumine salt of DELAXIANGHUASHUANG prepared in example 1 of the present invention;

FIG. 8 is an XRPD pattern for a novel crystalline form of the meglumine salt of delafloxacin prepared in example 1 of the present invention;

FIG. 9 is a TGA diagram of a novel crystalline form of the meglumine salt of delafloxacin prepared in example 1 of the present invention;

FIG. 10 is a DSC of a novel crystalline form of meglumine salt of delafloxacin prepared in example 1 of the present invention;

FIG. 11 is a TGA diagram of a novel crystalline form of the meglumine salt of delafloxacin prepared in example 4 of the present invention;

FIG. 12 is a DSC of a novel crystalline form of meglumine salt of delafloxacin prepared in example 4 of the present invention;

FIG. 13 is an XRPD pattern of a crystalline mixture of the novel crystalline Form of the meglumine salt of 1 DE-LAxacin according to the stability test of the invention and the crystalline Form of the anhydrous Form of the known Form 1A, form B of the meglumine salt of De-LAxacin after 7 days of stability competition.

Detailed Description

The present invention will be described in further detail with reference to the following examples and drawings in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

The instrument and the method for collecting data are as follows:

x-ray powder diffraction (XPRD): the instrument used was Bruker D8 Advance diffractometer, ka X-ray with copper target wavelength of 1.54nm was used, and under 40kV and 180mA operating conditions, a theta-2 theta goniometer, a Mo monochromator, a Lynxey detector. The instrument is calibrated prior to use with a standard (typically corundum) that the instrument is self-contained in. The sample is tested at room temperature and the sample to be tested is placed on a reflectionless plate. The detailed detection conditions are as follows, angular range: 3-50 degrees 2 theta, step length: 0.02 ° 2θ, speed: 0.12 seconds/step.

Differential thermal analysis (DSC) data was taken from METTLER TOLEDO DSC, the instrument control Software was STARe Software, and the analysis Software was STARe Software Application. Typically 1-10 mg of the sample is placed in a standard aluminum tray and the sample is raised from 0deg.C to 350deg.C at a rate of 10 deg.C/min under the protection of 50 mL/min dry nitrogen.

Thermogravimetric analysis (TGA) data was taken from METTLER TOLEDO TGA, instrument control Software was STARe Software and analysis Software was STARe Software Application. Typically 5-15 mg of the sample is placed in an aluminum crucible and the sample is warmed from room temperature to 350 ℃ under the protection of 40 mL/min dry nitrogen at a warming rate of 10 ℃/min.

The temperatures in the examples were room temperature unless otherwise specified.

In the examples, the ratio of the components in the mixed solvent is, for example, a volume ratio unless otherwise specified.

The delafloxacin, meglumine, solvents and reagents mentioned in the examples below are all commercially available.

Comparative example 1: preparation of crystalline form of delafloxacin meglumine salt anhydrate (preparation method of example 1 in WO2006042034 A2)

50Kg of DE-Lafloxacin and 21.6Kg of meglumine are added to 75.5Kg of water and 60.2Kg of isopropanol, dissolved at 45 ℃, cooled to 30+ -5 ℃, 175.7Kg of isopropanol is added, and the mixture is subjected to crystallization at 30 ℃. Filtering, washing the filter cake with isopropanol, vacuum drying at 30deg.C for 12h, and further drying at 50deg.C to obtain pale yellow solid as crude product of Grafloxacin meglumine salt.

The XRPD pattern is shown in figure 1, shown as crystalline;

the TGA profile is shown in fig. 2, showing: a weight loss of about 0.9% before 100 ℃ and about 8.5% at 100 ℃ to 250 ℃;

the DSC diagram is shown in fig. 3, showing: the melting point is about 172 ℃.

Comparative example 2: preparation of Derasagiline meglumine salt trihydrate form (preparation method of example 2 in WO2006042034A 2)

29.6Kg of DELASHIXIAN and 18.4Kg of meglumine are added into 133Kg of water, dissolved at 60 ℃, cooled to 38 ℃, stirred at a constant temperature until solid is separated out, and cooled to 0 ℃ for crystallization. Filtering, washing the filter cake with isopropanol, and vacuum drying at 50 ℃ to obtain a pale yellow solid.

The XRPD pattern is shown in fig. 4, shown as crystalline;

the TGA profile is shown in fig. 5, showing: a weight loss of about 7.8% before 110 ℃, and about 7.0% at 110 ℃ -240 ℃;

the DSC diagram is shown in fig. 6, showing: there is an endothermic peak before 120℃and the melting point is about 172 ℃.

Comparative example 3: preparation of delafloxacin meglumine salt Form 1A (preparation method of WO2014138639A 1)

100Kg of wet trihydrate prepared in comparative example 2 was dried in vacuo at 35℃for 17 hours, dried in vacuo at 55℃for 24 hours, then wetted with a stream of nitrogen gas at 40% -60% RH at 50-55℃until all of the crystals were formed into Form 1A, and dried in vacuo at 55℃for 48 hours after continuing to wet for 18 hours.

Comparative example 4: preparation of delafloxacin meglumine salt Form 1B (preparation method of WO2014138639A 1)

The trihydrate prepared in comparative example 2 was dried at 3mbar/30℃for 12h and then converted to Form 1B.

Example 1: preparation of novel crystal forms of Grafloxacin meglumine salt

1.5g of crude meglumine salt of DELAXfloxacin prepared in comparative example 1 was taken, 50mL of methanol and 50mL of acetone were added, the solution was stirred at 50℃and filtered through a membrane, and the solution was allowed to stand at 5℃overnight, whereby a solid was precipitated. Filtering, and baking at 50deg.C to obtain new crystal form with purity of 99.965% (HPLC spectrogram shown in figure 7) and yield of 56%. The XRPD pattern of which is shown in figure 8;

the TGA profile is shown in fig. 9, showing: a weight loss of about 2.3% before 120 ℃ and about 1.1% at 120 ℃ to 240 ℃;

the DSC diagram is shown in fig. 10, showing: the melting point is about 230 ℃.

Example 2: preparation of novel crystal forms of Grafloxacin meglumine salt

1.0g of crude product of the meglumine salt of the delafloxacin prepared in the comparative example 1 is taken, 50mL of methanol and 50mL of acetone are added, the mixture is stirred at 60 ℃ for about 1 hour, membrane filtration is carried out, solids are separated out, the mixture is stirred at 5 ℃ for 0.5 hour, suction filtration is carried out, and the material is dried at 70 ℃ for 22 hours, thus obtaining a new crystal form, and the yield is 56%.

Example 3: preparation of novel crystal forms of Grafloxacin meglumine salt

5.0g of crude product of the meglumine salt of the delafloxacin prepared in the comparative example 1 is taken, 125mL of methanol and 125mL of acetone are added, the mixture is stirred at 60 ℃ for about 0.5 hour, membrane filtration is carried out, solid precipitation is carried out, the mixture is stirred at 5 ℃ for 0.5 hour, suction filtration is carried out, and the material is baked at 70 ℃ for 16 hours, thus obtaining a new crystal form, and the yield is 56%.

Example 4: amplification preparation of new crystal form of Grafloxacin meglumine salt

20g of crude product of the meglumine salt of the DELAXIANGHUASHUANG prepared in comparative example 1 is taken, 420mL of methanol and 470mL of acetone are added, the mixture is stirred for about 1 hour at 64 ℃, membrane filtration is carried out, solids are separated out, suction filtration is carried out, the material is dried at 70 ℃ for 16 hours, and a new crystal form is obtained, the purity is 99.147%, and the yield is 56%.

The TGA profile is shown in fig. 11, showing: a weight loss of about 2.0% before 130 ℃;

the DSC diagram is shown in fig. 12, showing: the melting point is about 232 ℃.

Example 5: solvent residue detection in novel forms of meglumine salt of DELASORES

The crystalline form sample prepared in example 2 was subjected to solvent residue detection.

Gas Chromatography (GC) to detect the solvent residue of delafloxacin:

chromatographic column: agilent 123-1334DB-624 30m*0.53mm,3.0 μm. Flow rate: 3.5mL/min. Column temperature: the temperature was kept at 40℃for 5 minutes, at 10℃per minute to 120℃and at 20℃per minute to 260℃for 5 minutes. The temperature of the sample inlet is 230 ℃; detector (FID): a hydrogen flame ionization detector. The detector temperature was 230 ℃; the heating temperature of the headspace sample injection bottle is 95 ℃; the split ratio was 2/1. The diluent is DMSO. The sample injection amount was 2mL.

The solvent residues were measured as: methanol 0.011% (< 0.3%), acetone 0.053% (< 0.5%), detailed test results are shown in tables 1 and 2:

TABLE 1 detection results of solvent residue (methanol) for novel Crystal form magnification experiments

TABLE 2 detection results of solvent residue (acetone) for novel Crystal form magnification experiments

Example 6: preparation of tablets containing novel crystalline forms of the present invention of the meglumine salt of delafloxacin

The formulation of the tablet is as follows:

novel crystal forms of the invention of the meglumine salt of the DELAXfloxacin	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
Totals to	117.1g

The preparation steps of the tablet are as follows:

weighing 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 new crystal form of the meglumine salt of the DELASHUANG, and uniformly mixing; then adding 1g of magnesium stearate, and uniformly mixing; directly tabletting and coating.

Stability test 1

The stability competition experiment comparison is carried out on the novel crystal Form of the DELAXUANJIN salt and the known crystal forms of Form 1A, form B and DELAXUANJIN salt anhydrous substance, and the results are shown in Table 3.

The operation process of the stability competition experiment is as follows: equivalent (1 g) amounts of the novel crystalline Form of the delafloxacin meglumine salt prepared in any one of examples 1 to 4 of the present invention, the novel crystalline Form of the known delafloxacin meglumine salt prepared in comparative example 1, the novel crystalline Form of the known delafloxacin meglumine salt prepared in comparative example 3, form 1A of the known delafloxacin meglumine salt prepared in comparative example 4 and Form 1B of the known delafloxacin meglumine salt prepared in comparative example 4 are respectively taken, mixed, 15mL of methanol is added, after stirring for 7 days at room temperature, XRPD characterization is performed on the mixture (the measured XRPD pattern is shown in fig. 13), and only characteristic peaks of the novel crystalline Form of the delafloxacin meglumine salt of the present invention exist in the obtained XRPD pattern after analysis, and no characteristic peaks of the novel crystalline Form of the delafloxacin meglumine salt or the novel crystalline Form of the delafloxacin meglumine salt exist. The results of the competition experiments are thus shown in Table 3.

TABLE 3 stability competition experiment results

From the results in Table 3, it can be seen that: through stability competition experiments of crystal mush in a mixed solvent system of methanol and acetone at 40 ℃, the known delafloxacin meglumine salt anhydrous crystal Form is converted into the novel crystal Form of the delafloxacin meglumine salt, the known delafloxacin meglumine salt Form 1A is converted into the novel crystal Form of the delafloxacin meglumine salt, the known delafloxacin meglumine salt Form 1B is converted into the novel crystal Form of the delafloxacin meglumine salt, and the novel crystal Form of the delafloxacin meglumine salt of the invention keeps unchanged, so that the novel crystal Form of the delafloxacin meglumine salt of the invention is more stable than the novel crystal Form of the known delafloxacin meglumine salt anhydrous crystal Form, the known delafloxacin meglumine salt Form 1A and the known delafloxacin meglumine salt Form 1B.

Stability test 2

The stability test of the novel crystalline form of the meglumine salt of delafloxacin of the present invention was performed under the following conditions:

storage condition 1:

storing for 3 and 6 months in a sealed state at 40 ℃/75% rh;

storage condition 2:

storing for 1 and 3 months in an unsealed state at 40 ℃/75% rh;

as a result, the crystalline form and melting point of the novel crystalline form of the meglumine salt of delafloxacin of the present invention were unchanged as measured by XRPD and DSC after 3 months under storage condition 1 and after 1 month under storage condition 2; after 6 months under the storage condition 1 and 3 months under the storage condition 2, the crystal form and the melting point of the novel crystal form of the meglumine salt of the delafloxacin of the invention are further detected by XRPD and DSC to be unchanged;

on the other hand, the total amount of impurities in the novel crystalline form of the meglumine salt of delafloxacin of the present invention was unchanged throughout the test period compared to before the start of the test.

Comparative test

The crude products of the meglumine salt of the delafloxacin prepared in the comparative example 1 are respectively taken, added with the solvents with the amounts shown in the following table 4, placed in a constant temperature stirrer, heated to 50 ℃, stirred and observed under the constant temperature, and the dissolution condition is recorded.

TABLE 4 Table 4

Quality of	Solvent(s)	Volume of	Phenomenon (1)
				3.0g	Methanol	150mL	Undissolved clear
2.0g	Acetone (acetone)	120mL	Undissolved clear
				1.5g	Methanol + acetone	50mL+50mL	Solution cleaner

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

Unless otherwise stated, percentages stated throughout this application are weight/weight (w/w) percentages.

The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principle of the invention, and these improvements and modifications fall within the scope of the claims of the invention.

Claims

1. A novel crystal form of a meglumine salt of delafloxacin, which is characterized in that Cu-K alpha radiation is used, and an X-ray powder diffraction pattern of the novel crystal form 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 novel crystalline form of the meglumine salt of delafloxacin according to claim 1, further characterized by an X-ray powder diffraction pattern having 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 novel crystalline form of the meglumine salt of delafloxacin according to claim 2, further characterized by an X-ray powder diffraction pattern having one or more diffraction peaks at the following 2Θ angles: 21.279 + -0.2 DEG, 22.140 + -0.2 DEG,

22.718±0.2°、23.801±0.2°、25.820±0.2°、27.100±0.2°。

4. A new crystalline form of meglumine salt of delafloxacin according to claim 3, further characterized by having an X-ray powder diffraction pattern substantially the same as figure 8.

5. A process for the preparation of a novel crystalline form of meglumine salt of delafloxacin according to claim 5, comprising the steps of:

dissolving crude product of Grafloxacin meglumine salt in mixed solvent of alcohols and esters/ketones/ethers/alkanes, stirring, membrane filtering to obtain solid, filtering, and oven drying.

6. The preparation process according to claim 6, wherein the crude salt of delafloxacin meglumine salt is preferably amorphous Form of delafloxacin meglumine salt or crystalline Form of delafloxacin meglumine salt, more preferably crystalline Form of delafloxacin meglumine salt anhydrate or crystalline Form of delafloxacin meglumine salt trihydrate, more preferably crystalline Form of delafloxacin meglumine salt anhydrate, particularly preferably crystalline Form of delafloxacin meglumine salt as described in WO2006042034A2, form 1A as described in WO2014138639A1, or Form 1B as described in WO2014138639A1, most preferably crystalline Form of delafloxacin meglumine salt as described in WO2006042034 A2;

and/or the alcohol solvent is preferably one or two of methanol and ethanol, more preferably methanol or ethanol, and most preferably methanol;

and/or 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 one of acetone, ethyl acetate, diethyl ether, isopropyl ether methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, acetonitrile, dichloromethane, chloroform, methylcyclohexane, most preferably acetone;

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

and/or the temperature at which the stirring is carried out may be from 40 to 70 ℃, preferably from 50 to 64 ℃, most preferably 64 ℃;

and/or the stirring time is from stirring to dissolving, more preferably from 0.5 to 1 hour, most preferably 1 hour;

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

and/or, the membrane filtration may further comprise a still filtration after and before solid precipitation, preferably at 5 ℃;

and/or the temperature at which the material is baked is from 30 to 100 ℃, preferably from 50 to 70 ℃, most preferably 70 ℃;

and/or the drying time is 12 to 24 hours, preferably 12 to 20 ℃, more preferably 14 to 18 ℃, more preferably 15 to 17 ℃, and most preferably 16 hours.

7. A process for the preparation of a novel crystalline form of meglumine salt of delafloxacin according to claim 5, comprising the steps of: adding mixed solvent of methanol and acetone with the volume ratio of 0.5:1-1:0.5 into the crude product of the meglumine salt of the DE-LASHUAXUE to dissolve into solution with the concentration of 10 mg/mL-30 mg/mL, stirring at 40-70 ℃, membrane filtering, separating out solids, pumping filtering and drying.

8. A tablet comprising the novel crystalline form of the meglumine salt of delafloxacin according to claim 5 or obtained by the process of preparation according to any one of claims 6 to 8, and at least one pharmaceutically acceptable carrier or adjuvant.

9. Use of the novel crystalline form of the meglumine salt of delafloxacin according to claim 5 or of the novel crystalline form of the meglumine salt of delafloxacin according to the invention obtained by the process of preparation according to any one of claims 6 to 8 for the preparation of a medicament for the treatment and/or prophylaxis of bacterial infections.