CN107353304B - Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal form A, preparation method and application - Google Patents
Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal form A, preparation method and application Download PDFInfo
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- CN107353304B CN107353304B CN201710565619.0A CN201710565619A CN107353304B CN 107353304 B CN107353304 B CN 107353304B CN 201710565619 A CN201710565619 A CN 201710565619A CN 107353304 B CN107353304 B CN 107353304B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of Tedizolid Phosphate Tris salt and its crystal form A, preparation method and application, the water solubility of Tedizolid Phosphate Tris salt and its crystal form A of the invention and stability is good, low in hygroscopicity, it can be used for preparing oral preparation and injection, there is important application value in preparing antibiotic medicine.
Description
Technical field
The invention belongs to field of medicaments, and in particular to the trishydroxymethylaminomethane salt (Tris salt) of the safe ground azoles amine of phosphoric acid and
Its crystal form A, preparation method and application.
Background technique
Since penicillin comes out, the mankind have developed a antibacterials up to a hundred, the treatment for bacterial infection.With
These drugs being widely used and abusing, the drug resistance rapid increase of bacterium, this after the 1990s
Speed researches and develops the speed of antibacterials significantly more than the mankind, and the mankind, which have gone around the circle, is returned to original place, faces " when rear antibiotic
In generation ", seriously threatens.In order to avoid the crossing drug resistant with existing antibacterials, it is therefore desirable to which developing has the complete of different role mechanism
New antimicrobial agent.
Oxazolidinones antibacterials are exactly this kind of fully synthetic antibacterials with novel mechanism, have been had at present
Linezolid (2000) and phosphoric acid safe ground azoles amine (2014) two oxazolidinones drugs are ratified to list through FDA.Research knot
Fruit shows, phosphoric acid safe ground azoles amine is lower compared to the incidence of Linezolid drug resistance, and dosage is smaller, and usage is once a day totally six
It, than Linezolid totally ten days application methods are more convenient twice daily, treatment cycle is shorter, is a kind of excellent overriding resistance
Bacterium drug.Azoles amine shared oral and two kinds of dosage forms of freeze-dried powder in phosphoric acid safe ground take orally using phosphoric acid safe ground azoles amine free acid,
Because its is not soluble in water for free acid, freeze-dried powder is to convert water-soluble disodium salt for phosphoric acid safe ground azoles amine free acid tune pH value,
Shown in phosphoric acid safe ground azoles amine structure formula such as formula (II):
Crystal form research is an essential component part of modern pharmacy research.Te Liusi acology company, the U.S. exists
Chinese patent CN102439006A discloses a kind of crystal form of phosphoric acid safe ground azoles amine free acid.
Another new phosphoric acid safe ground azoles amine free acid crystal form is described in patent WO2015158202, in patent
In WO2015158202, in order to distinguish the crystal form of Te Liusi company, it is named as crystal form II, the crystal form name of Te Liusi company
It is pointed out simultaneously for crystal form I, patent WO2015158202, phosphoric acid safe ground azoles amine free acid especially crystal form I is moist with drawing, and adopts
Analysis method is DVS detection, and crystal form I weight change in 20%-80% RH range is 1.58%, and crystal form II exists
Weight change is 0.49% in 20%-80% RH range.
In addition, another crystal form of phosphoric acid safe ground azoles amine free acid is also disclosed in Chinese patent CN105646582A, it should
Also indicated that in patent, the crystal form of Te Liusi have it is stronger draw moist, and its new crystal form, detect and find by DVS,
Drawing wet weight gain under 80% relative humidity is 0.3%.
A kind of crystal form of phosphoric acid safe ground azoles amine disodium salt is disclosed in Chinese patent CN104530128B, which describes,
The safe ground azoles amine disodium salt of phosphoric acid draw it is moist be even stronger than its free acid, cause disodium salt to be not suitable for being peroral dosage form, while two
Sodium salt stability is poor, and injection can only be made into freeze-dried powder, and the phosphoric acid safe ground azoles amine disodium salt crystal form product presses Chinese Pharmacopoeia
Draws moist test detection, it is 1.2%-1.7% that wet weight gain is drawn under 80% relative humidity, be classified as slightly drawing it is moist, according to spy
It is 16.6% that the amorphous products that method synthesizes in Liu Si company Chinese patent application 200980140144.4, which draw wet weight gain, classification
For it is great draw it is moist.
Three kinds of crystal forms of phosphoric acid safe ground azoles amine disodium salt are disclosed in Chinese patent CN104558034A, are not directed in patent
Draw moist problem and detection.In general, if active constituent draw it is moist too strong, in oral solid formulation processing, the easy sticking of tabletting,
Poor fluidity, content generate big error.
A kind of injection phosphoric acid safe ground azoles amine is disclosed in Chinese patent CN105287407, patent description is due to phosphoric acid Thailand
Ground azoles amine free acid is not water-soluble, when preparing freeze-dried powder, it need to be converted into disodium salt under alkaline condition, however, phosphoric acid
The moisture of safe ground azoles amine freeze-dried powder needs especially control, and otherwise disodium salt can be hydrolyzed into formula III hydroxylic species not soluble in water, can
Injection can be caused muddy, clarity is unqualified, brings drug safety problem.Degradation mode is shown below:
For this reason, it is necessary to develop it is new be unlikely to be wetted and the pharmaceutically acceptable water soluble salt of stable phosphoric acid safe ground azoles amine, with
It solves the above problems.
Summary of the invention
The purpose of the present invention is to provide a kind of water-soluble and stability more preferably, draws moist lower while being suitble to do oral
The phosphoric acid of preparation and injection safe ground azoles amine Tris salt and its crystal form.
The present invention provides a kind of phosphoric acid safe ground azoles amine Tris salt, referred to herein as formula (I) compound, structural formula is as follows:
The present invention also provides a kind of crystal form A of formula (I) compound, referred to herein as crystal form A.Crystal form A of the invention is in X-
In ray powder diffraction comprising following 2 θ angle of reflection measurement characteristic peak: 15.2 ± 0.2 °, 18.5 ± 0.2 °, 20.6 ±
0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°。
Preferably, the spy that crystal form A of the invention is also measured comprising following 2 θ angle of reflection in the X-ray powder diffraction pattern
Sign peak: 6.9 ± 0.2 °, 16.4 ± 0.2 °, 19.4 ± 0.2 °, 21.9 ± 0.2 °.
Preferably, the X-ray powder diffraction collection of crystal form A of the invention is as shown in Figure 3.
The present invention also provides the preparation methods of a kind of formula (I) compound and its crystal form A, comprising the following steps:
Trishydroxymethylaminomethane is dissolved in organic solvent I, solution I is obtained.Phosphoric acid safe ground azoles amine free acid is dissolved in two
In first sulfoxide, solution II is obtained.Solution I and solution II are mixed, crystallization is stood, filters, is dried to obtain formula (I) compound crystal form A.
Preferably, the organic solvent I is acetone, acetonitrile, tetrahydrofuran, dioxane, C1-C3Alkylol (including
Methanol, ethyl alcohol, propyl alcohol or isopropanol) one of or a variety of combinations.As a further preference, the organic solvent I
For methanol.
The present invention also provides a kind of pharmaceutical compositions comprising formula (I) compound and/or its crystal form A, and it is a kind of or more
The pharmaceutical carrier of kind.
Preferably, one or more pharmaceutical carriers are inert non-toxic carrier, wherein the inert non-toxic
Carrier can be selected according to the existing knowledge of those skilled in the art, including diluent pharmaceutically used, adhesive, be collapsed
Solve agent, lubricant and glidant etc., such as starch, gelatin, crospovidone, magnesium stearate and colloidal silicon dioxide etc..
The present invention also provides formula (I) compounds and its crystal form A to prepare the application in antibiotic medicine.
The present invention also provides a kind of pharmaceutical preparations comprising formula (I) compound of the present invention and/or formula (I) are changed
The crystal form A of object is closed, wherein the pharmaceutical preparation is oral preparation or injection.
The crystal form A of formula (I) compound of the invention is very stable in ambient enviroment, and water-soluble and stability is safe better than phosphoric acid
Ground azoles amine disodium salt, and it is substantially moist without drawing, it can be used to prepare oral preparation and injection simultaneously；Preparation process reproducibility
It is fabulous, it is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of formula (I) compound of the invention.
Fig. 2 is formula (I) compound high resolution mass spectrum of the invention.
Fig. 3 is the powder x-ray diffraction map of formula (I) compound crystal form A of the invention.
Fig. 4 is the TG map of formula (I) compound crystal form A of the invention.
Fig. 5 is the DSC map of formula (I) compound crystal form A of the invention.
Specific embodiment
Illustrate specific embodiments of the present invention referring to the following example, these embodiments be to illustrate the present invention, and
It is non-to limit the invention in any way.
Raw material phosphoric acid used in the following embodiment safe ground azoles amine free acid is purchased from Jinan Xuan De Chemical Co., Ltd..
Formula (I) compound nucleus magnetic hydrogen spectrum testing conditions:
III 500 type Nuclear Magnetic Resonance of Zhejiang University Brucker Avance is (with D2O is solvent, and TMS is internal standard).
Formula (I) compound high resolution mass spectrum testing conditions:
Zhejiang University's AB Sciex Triple TOF 5600+ quadrupole rod time of-flight mass spectrometer.Ion source is ESI, just
Ion mode scanning.
The X-ray powder diffraction spectrometry instrument and determination condition of formula (I) compound crystal form A:
Determining instrument: Zhejiang University EMPYREAN type diffractometer, PANALYTICAL
Determination condition:
Heat analysis (the TG and DSC) determining instrument and determination condition of formula (I) compound crystal form A:
TG: TA company, the U.S., Zhejiang University SDT Q600 heat analysis detector.Alpha-alumina is control, heating rate: 10
℃/min.Atmosphere: nitrogen.
DSC: TA company, the U.S., Zhejiang University DSC Q100 heat analysis detector.Blank aluminium crucible is to compare, heating rate:
10℃/min.Atmosphere: nitrogen.
The preparation of embodiment 1 formula (I) compound crystal form A
Trishydroxymethylaminomethane (1.62g, 13.37mmoL) is mixed with methanol (80mL), and stirring and dissolving obtains solution I.Phosphorus
Sour safe ground azoles amine free acid (3g, 6.66mmoL) mixes with dimethyl sulfoxide (9mL), and stirring and dissolving obtains solution II.By solution I and
II is mixed at room temperature, static crystallization, is filtered, vacuum drying.Obtain formula (I) compound crystal form A, structural identification nuclear magnetic resonance figures
Spectrum, mass-spectrogram difference are as depicted in figs. 1 and 2, and crystal form identifies powder x-ray diffraction map, TG map and DSC map such as
Shown in Fig. 3~5.
In the powder x-ray diffraction determination data table 1 listed below of formula (I) compound crystal form A.
Table 1
The preparation of embodiment 2 formula (I) compound crystal form A
Trishydroxymethylaminomethane (1.62g, 13.37mmoL) is mixed with methanol (80mL), and stirring and dissolving obtains solution I.Phosphorus
Sour safe ground azoles amine free acid (3g, 6.66mmoL) mixes with dimethyl sulfoxide (9mL), and stirring and dissolving obtains solution II.By solution I and
II is mixed at room temperature, adds acetone (160mL) stirring, and static crystallization filters, and vacuum drying obtains formula (I) compound crystal form
A, nuclear magnetic resonance map, mass-spectrogram, powder x-ray diffraction map, TG map and DSC map respectively with Fig. 1, Fig. 2, figure
3, Fig. 4 and Fig. 5 are consistent.
The preparation of embodiment 3 formula (I) compound crystal form A
Trishydroxymethylaminomethane (1.62g, 13.37mmoL) is mixed with ethyl alcohol (100mL), and stirring and dissolving obtains solution I.
Phosphoric acid safe ground azoles amine free acid (3g, 6.66mmoL) is mixed with dimethyl sulfoxide (9mL), and stirring and dissolving obtains solution II.By solution I
It mixes, static crystallization, filters at room temperature with II, vacuum drying obtains formula (I) compound crystal form A, nuclear magnetic resonance map, matter
Spectrogram spectrum, powder x-ray diffraction map, TG map and DSC map are consistent with Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5 respectively.
The preparation of embodiment 4 formula (I) compound crystal form A
Trishydroxymethylaminomethane (1.62g, 13.37mmoL) is mixed with acetonitrile (110mL), and stirring and dissolving obtains solution I.
Phosphoric acid safe ground azoles amine free acid (3g, 6.66mmoL) is mixed with dimethyl sulfoxide (9mL), and stirring and dissolving obtains solution II.By solution I
It mixes, static crystallization, filters at room temperature with II, vacuum drying obtains formula (I) compound crystal form A, nuclear magnetic resonance map, matter
Spectrogram spectrum, powder x-ray diffraction map, TG map and DSC map are consistent with Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5 respectively.
The disodium of 1 phosphoric acid of experimental example safe ground azoles amine Tris salt crystal form A (formula (I) compound crystal form A) and phosphoric acid safe ground azoles amine
The quality of salt compares
To (I) the compound crystal form A of formula made from the application method and by the safe ground of the phosphoric acid of patent CN104530128B preparation
Azoles amine disodium salt crystal form product and amorphous products carry out solubility, draw moist and accelerated test, testing conditions are as follows:
Solubility test condition: weighing test sample, in the water of 25 ± 2 DEG C of certain capacities.Every strength concussion 30 in 5 minutes
Second, the dissolution situation in observation 30 minutes is considered as and is completely dissolved when as without visual visible particles of solute.It is easily molten to refer to
1g test sample dissolves in less than 1mL water, readily soluble to refer to that 1g test sample dissolves in 1~10mL water.
Draws moist test condition: weighing in dry tool plug glass, is placed in suitable thermostatic drier in test the previous day
It is interior, 25 ± 1 DEG C of set temperature, relative humidity 80 ± 2%, accurately weighed weight (m1).It takes test sample appropriate, is laid in above-mentioned title
In measuring bottle, test sample thickness is about 1mm, accurately weighed weight (m2).It is placed in above-mentioned constant temperature together by weighing bottle opening, and with bottle cap
24 hours under the conditions of constant humidity.Cover weighing bottle lid, accurately weighed weight (m3).
Draw moist weight gain to define:
It is great draw it is moist: draw wet weight gain not less than 15%；
Somewhat draw moist: drawing wet weight gain less than 2% but not less than 0.2%；
Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%.
Accelerated stability test condition: it by double aluminium packagings, is put under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%
It sets 3 months, liquid chromatographic detection purity and related substance.
Testing result is as follows:
Test result shows Tris salt crystal form A that the present processes obtain in water-soluble, stability and draws moist side
Face, effect are all obviously improved.
Claims (8)
1. a kind of crystal form A of formula (I) compound, which is characterized in that the crystal form A of formula (I) compound spreads out in X-ray powder
Penetrate in map comprising following 2 θ angle of reflection measurement characteristic peak: 6.9 ± 0.2 °, 15.2 ± 0.2 °, 16.4 ± 0.2 °, 18.5 ±
0.2°、19.4±0.2°、20.6±0.2°、21.9±0.2°、24.8±0.2°、25.5±0.2°、26.5±0.2°
2. a kind of preparation method of the crystal form A of formula as described in claim 1 (I) compound, which is characterized in that including following step
It is rapid:
Trishydroxymethylaminomethane is dissolved in organic solvent I, solution I is obtained；Phosphoric acid safe ground azoles amine free acid is dissolved in diformazan Asia
In sulfone, solution II is obtained；Solution I and solution II are mixed, crystallization is stood, filters, be dried to obtain the crystalline substance of described formula (I) compound
Type A.
3. the preparation method of the crystal form A of formula (I) compound according to claim 2, which is characterized in that described is organic molten
Agent I is acetone, acetonitrile, tetrahydrofuran, dioxane, C1-C3One of alkylol or a variety of combinations.
4. the preparation method of the crystal form A of formula (I) compound according to claim 3, which is characterized in that described is organic molten
Agent I is methanol.
5. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes formula as described in claim 1 (I) chemical combination
The crystal form A of object and one or more pharmaceutical carriers.
6. pharmaceutical composition described in the crystal form A or claim 5 of a kind of formula described in claim 1 (I) compound is being made
Application in standby antibiotic medicine.
7. a kind of pharmaceutical preparation, which is characterized in that the pharmaceutical preparation includes the crystalline substance of formula described in claim 1 (I) compound
Type A.
8. pharmaceutical preparation according to claim 7, which is characterized in that the pharmaceutical preparation is oral preparation or injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710565619.0A CN107353304B (en) | 2017-07-12 | 2017-07-12 | Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal form A, preparation method and application |
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| CN201710565619.0A CN107353304B (en) | 2017-07-12 | 2017-07-12 | Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal form A, preparation method and application |
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Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015054246A1 (en) * | 2013-10-07 | 2015-04-16 | Trius Therapeutics, Inc. | Methods of treating subjects with renal impairment using tedizolid |
| CN105418678B (en) * | 2014-09-17 | 2018-11-20 | 正大天晴药业集团股份有限公司 | A kind of preparation method of Tedizolid Phosphate |
| CN105646582A (en) * | 2014-11-20 | 2016-06-08 | 苏州晶云药物科技有限公司 | Tedizolid phosphate crystal form I and preparation method thereof |
| WO2016088102A1 (en) * | 2014-12-05 | 2016-06-09 | Sun Pharmaceutical Industries Limited | Processes for the preparation of tedizolid phosphate and its intermediates |
| WO2016088103A1 (en) * | 2014-12-05 | 2016-06-09 | Sun Pharmaceutical Industries Limited | A process for the preparation of tedizolid phosphate |
| CN104530128B (en) * | 2014-12-30 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | A kind of Tedizolid Phosphate disodium salt and preparation method thereof |
| CN104558034A (en) * | 2015-01-21 | 2015-04-29 | 齐鲁制药有限公司 | Novel crystal form of tedizolid phosphate disodium salt and preparation method of novel crystal form |
| CN106146558A (en) * | 2015-04-10 | 2016-11-23 | 博瑞生物医药（苏州）股份有限公司 | New oxazolidinones and preparation method thereof |
| CN106236718A (en) * | 2016-08-29 | 2016-12-21 | 海南通用康力制药有限公司 | A kind of pharmaceutical composition of Tedizolid Phosphate and preparation method thereof |
| CN106632481B (en) * | 2016-09-09 | 2018-05-29 | 优胜美特制药有限公司 | Crystal form A of Yi Zhong oxazolidinone antibacterials and its preparation method and application |
| CN106749321B (en) * | 2017-01-17 | 2018-10-09 | 浙江普洛得邦制药有限公司 | The crystal form B and its preparation method and application of Yi Zhong oxazolidinone antibacterials sodium salts |
| CN107226825B (en) * | 2017-06-14 | 2019-08-02 | 浙江海正药业股份有限公司 | Phosphoric acid safe ground azoles amine ammonium salt and its crystal form, preparation method and medical usage |
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Effective date of registration: 20200628 Address after: No.399, Jiangnan Road, Hengdian Town, Dongyang City, Jinhua City, Zhejiang Province Co-patentee after: SHANDONG APELOA PHARMACEUTICAL Co.,Ltd. Patentee after: APELOA PHARMACEUTICAL Co.,Ltd. Co-patentee after: ZHEJIANG APELOA TOSPO PHARMACEUTICAL Co.,Ltd. Address before: 322118, 519, Zhenjiang South Road, Dongyang, Zhejiang, Jinhua, Hengdian Co-patentee before: SHANDONG APELOA PHARMACEUTICAL Co.,Ltd. Patentee before: ZHEJIANG APELOA TOSPO PHARMACEUTICAL Co.,Ltd. |