CN106866702A - Crystal formation of De Luogewei sodium salts and preparation method thereof - Google Patents

Crystal formation of De Luogewei sodium salts and preparation method thereof Download PDF

Info

Publication number
CN106866702A
CN106866702A CN201710242414.9A CN201710242414A CN106866702A CN 106866702 A CN106866702 A CN 106866702A CN 201710242414 A CN201710242414 A CN 201710242414A CN 106866702 A CN106866702 A CN 106866702A
Authority
CN
China
Prior art keywords
crystal formation
sodium salts
luogewei sodium
luogewei
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710242414.9A
Other languages
Chinese (zh)
Other versions
CN106866702B (en
Inventor
宋小叶
盛晓霞
盛晓红
贾强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd
Original Assignee
HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd filed Critical HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
Publication of CN106866702A publication Critical patent/CN106866702A/en
Application granted granted Critical
Publication of CN106866702B publication Critical patent/CN106866702B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to the novel crystal forms of De Luogewei sodium salts.Compared to the known crystal formation of De Luogewei sodium salts, novel crystal forms of the invention have one or more of beneficial property, and such as water stability is good, solubility is high, be difficult moisture absorption, excellent storage stability, granule-morphology are good.Preparation method, its pharmaceutical composition the invention further relates to the De Luogewei sodium salts novel crystal forms and its for the purposes in the medicine for preparing treatment and/or the prevention infection of HIV 1.

Description

Crystal formation of De Luogewei sodium salts and preparation method thereof
The application is the Application No. 201580000497.X (PCT/CN2015/ that on October 10th, 2015 enters China 074293, international filing date on March 16th, 2015) patent application " crystal formation of De Luogewei sodium salts and preparation method thereof " point Case application.
Technical field
The present invention relates to medicine crystal technical field.Crystal formation and its preparation side in particular to De Luogewei sodium salts Method.
Background technology
De Luogewei (English name dolutegravir) is GlaxoSmithKline PLC drugmaker public with Japan's Shionogi A kind of new hiv integrase inhibitor that department researches and develops hand in hand, the inhibitor is intended to by the diffusion for suppressing virus so as to treat Chinese mugwort Grow disease.It obtains U.S. FDA approval and lists in August, 2013, trade name TIVICAY, and sodium salt containing De Luogewei is 50mg oral tablets Agent.The medicine is approved the extensive crowd for HIV, i.e., before never received HIV therapy and received anti-hiv therapy Infected patient, including have been used by before other integrase inhibitors treatment HIV patient can apply.The medicine also goes through For at least 40 kilograms of 12 years old age and the above, body weight, do not treated or passed through treatment but do not received other integrases and pressed down The children of preparation for treating, the recommended dose to above-mentioned child patient is 50mg, and oral one time a day.
The chemical name of De Luogewei sodium salts is：(4R, 12aS) -9- { [(2,4 difluorobenzene base) methyl] carbamyls Base } -4- methyl -6,8- dioxo -3,4,6,8,12,12a- hexahydro -2H- pyridos [1', 2':4,5] pyrazine is simultaneously [2,1-b] [1,3] oxazine -7- sodium alkoxides；English name is：Dolutegravir sodium or GSK1349572, chemical formula is： C20H18F2N3NaO5；Molecular weight is：441.36；Chemical structural formula is as follows：
Patent document WO2010/068253A1 and WO2012/018065A1 disclose De Luogewei and preparation method thereof. WO2010/068253A1 also discloses De Luogewei sodium salts and its monohydrate, and uses solid-state13C-NMR, XRPD and IR are to moral sieve The crystal formation of Ge Wei, De Luogewei sodium salt and De Luogewei sodium salt monohydrates is characterized.For ease of distinguishing, will in the present invention The crystal formation of De Luogewei sodium salts disclosed in WO2010/068253A1 is referred to as " crystal formation I ".
Patent document WO2013/038407A1 discloses amorphous article of De Luogewei sodium salts and preparation method thereof, is used in combination XRPD, DSC, TGA, FTIR, FT-Raman are characterized to it.
The present inventor is to De Luogewei sodium salts crystal formation I, De Luogewei sodium salt monohydrate and moral Roger disclosed in document Wei sodium salt amorphous article has carried out repeating experiment and nature examination, as a result shows：De Luogewei sodium salt crystal formation I and De Luogewei sodium The stability of salt monohydrate is bad, and original crystal habit, and they can not be maintained in water stability competitive assay Dissolubility it is relatively low, with certain hygroscopicity, such property cause its pharmaceutical preparation exist activity substance content it is unstable, The problems such as impurity content increases in production poor reproducibility, storage process, drug effect declines.Additionally, De Luogewei sodium salt amorphous articles In water, at room temperature stir 5 minutes i.e. be changed into crystal formation I, stability is very poor, is not suitable for solid pharmaceutical preparation application.
In order to meet strict demand of the pharmaceutical preparation for active constituents of medicine form, expand the original selected by formulation development Material form, this area stills need to develop the novel crystal forms of De Luogewei sodium salts.
The content of the invention
In view of the shortcomings of the prior art, the purpose of the present invention is the novel crystal forms by providing De Luogewei sodium salts, is solved Know the problem that crystal formation is present.Meanwhile, the invention further relates to the preparation method and its pharmaceutical composition and purposes of the novel crystal forms.
The novel crystal forms compared with known crystal formation, with least one following favorable property：Good stability, such as crystal formation Stability, thermal stability, chemical stability, mechanical stability, bin stability etc.；Dissolubility is good；Dissolution rate is fast；Crystallization Degree is high；It is difficult moisture absorption；It is easy to purify and processes；Chemical purity is high；Low-residual solvent；Granule-morphology is good；Suitable preparation can add It is work such as good fluidity, favourable powder viscosity, tight ness rating and rammability, apparent good；Improve bioavilability, preparation medicine Effect；Extension preparation storage life；It is adapted to the aspects such as novel form application.
Purpose of the invention, the crystal formation A that the present invention provides De Luogewei sodium salts (is referred to as " crystal formation in the present invention A”)。
The crystal formation A is the anhydride of De Luogewei sodium salts, and its structural formula is as follows：
Radiated using Cu-K α, the crystal formation A has with the X-ray powder diffraction collection that 2 θ angles are represented in following position Characteristic peak：6.4 ± 0.2 °, 9.0 ± 0.2 °, 9.3 ± 0.2 °, 13.9 ± 0.2 °, 19.2 ± 0.2 ° and 21.8 ± 0.2 °.
Preferably, the crystal formation A has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 6.4±0.2°、7.9±0.2°、9.0±0.2°、9.3±0.2°、11.6±0.2°、13.9±0.2°、15.2±0.2°、15.9 ± 0.2 °, 16.4 ± 0.2 °, 19.2 ± 0.2 °, 21.8 ± 0.2 ° and 28.7 ± 0.2 °.
It is highly preferred that the crystal formation A has feature with the X-ray powder diffraction collection that 2 θ angles are represented in following position Peak and relative intensity：
Without limitation, a representative instance of the crystal formation A has X-ray powder diffraction figure as shown in Figure 10.
The FTIR spectrum of the crystal formation A wave number be 2942,1641,1537,1503,1424,1321,1278, 1258th, 1094,1069,964,854,763 and 722cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation A shows：Sample is anhydride weightless 1.0% before 150 DEG C, point Solution temperature is 366 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal formation A shows：It starts fusion and decomposition at 312 DEG C.
The preparation method of the crystal formation A, comprises the following steps：By known De Luogewei sodium salts in water and organic solvent Suspension is formed in mixed solvent, wherein the organic solvent is selected from acetonitrile, Isosorbide-5-Nitrae-dioxane, acetone, butanone or its mixing Thing, water is 3 with the volume ratio of organic solvent:1~5:1, stirring and crystallizing, the crystal that will be separated out is separated, dried, and obtains the crystal formation A。
Preferably, the organic solvent is acetonitrile or Isosorbide-5-Nitrae-dioxane.
Preferably, the water and the volume ratio of organic solvent are 4:1~5:1.
Preferably, the temperature of the crystallization is 10~60 DEG C, more preferably 40~60 DEG C.
Preferably, the time of the crystallization is 5~14 days, more preferably 5~8 days.
Preferably, in the suspension consumption of known De Luogewei sodium salts for it is molten in the mixing under recrystallization temperature 2~10 times of solubility, more preferably 2~5 times in agent.
Preferably, the dry temperature is 10~60 DEG C, more preferably 10~40 DEG C.
Preferably, the dry time is 10~48 hours, more preferably 10~24 hours.
The preparation method of above-mentioned crystal formation A employs the crystallization mode of magma, is that (supersaturated solution of sample is had into insoluble Solid presence) stir in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal formation A, the known De Luogewei sodium salts, including published De Luogewei sodium salts Various crystal formations or amorphous article, for example include but is not limited to according to patent document WO2010068253A1 embodiment 1l description sides De Luogewei sodium salt crystal formation I prepared by method, or prepared according to 3.1 method I of patent document WO2013038407A1 embodiments 1 De Luogewei sodium salt amorphous articles.
Crystal formation A has following beneficial property：
1. contrasted by the stability competitive assay of the magma in water, it is known that De Luogewei sodium salt crystal formation I and moral Roger Wei sodium salt monohydrate can not maintain original crystal habit, be transformed into crystal formation A, and crystal formation A is protected under same experiment condition Hold crystal formation constant.
2. crystal formation A is placed 4 months in room temperature, the drier of 10%~90%RH of relative humidity, and crystal formation and fusing point are not Become.
3. after crystal formation A is stored 10 days under 80 DEG C of hot and humid illumination conditions of -90%RH-6000lx, under its purity The growth of drop and maximum single miscellaneous content all significantly lower than the data of known De Luogewei sodium salt crystal formations I, illustrate its stability compared with Known De Luogewei sodium salts crystal formation I is good.
4. compared with known Roger's Wei sodium salt monohydrate, crystal formation A of the invention is in 20%-80% RH ranges Interior weight change is 1.0% (known monohydrate weight change in 20%-80% RH ranges is 4.3%), is said Bright crystal formation A of the invention is less susceptible to moisture absorption.
The above-mentioned property of crystal formation A shows：With known De Luogewei sodium salts crystal formation I and De Luogewei sodium salt monohydrate phase Than crystal formation A good stabilities of the invention.Crystal formation A has more preferable stability in water, is more suitable for the wet granulation of solid pharmaceutical preparation Technique is made oral administration mixed suspension, has good preparation machinability in Aquo System；The excellent storage stability of crystal formation A, The environmental condition of looser manufacture, storage and transport is suitable for, its preparation can be resisted preferably due to temperature, humidity, crystalline substance Type change etc. is the problems such as the issuable active constituents of medicine content of factor is uneven, purity declines, the treatment that thus reduction brings Effect downside risk and security risk.
Purpose of the invention, the present invention provides the monohydrate crystal form B of De Luogewei sodium salts (in the present invention referred to as It is " crystal formation B ").
The crystal formation B is the hydrate of De Luogewei sodium salts, and every mole of crystal formation B contains about 1 mole of water, and its structural formula is such as Shown in lower：
Radiated using Cu-K α, the crystal formation B has with the X-ray powder diffraction collection that 2 θ angles are represented in following position Characteristic peak：7.9 ± 0.2 °, 9.0 ± 0.2 °, 11.1 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 ° and 22.4 ± 0.2 °.
Preferably, the crystal formation B has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 7.9±0.2°、9.0±0.2°、11.1±0.2°、13.8±0.2°、15.1±0.2°、15.9±0.2°、18.1±0.2°、 22.4 ± 0.2 °, 22.7 ± 0.2 °, 23.4 ± 0.2 °, 26.0 ± 0.2 ° and 26.3 ± 0.2 °.
It is highly preferred that the crystal formation B has feature with the X-ray powder diffraction collection that 2 θ angles are represented in following position Peak and relative intensity：
Without limitation, a representative instance of the crystal formation B has X-ray powder diffraction figure as shown in figure 16.
The FTIR spectrum of the crystal formation B wave number be 2968,1645,1537,1502,1424,1320,1278, 1258th, 1095,1068,964,875,846,762 and 731cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation B shows：Sample is hydrate；Weightless 6.2% (contains before 150 DEG C Surface water 2.0%), it is roughly equal to containing a molecular water, decomposition temperature is about 369 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal formation B shows：It starts fusion and decomposition at 349 DEG C.
The preparation method of the crystal formation B, comprises the following steps：De Luogewei sodium salts is molten with the mixing of organic solvent in water Suspension is formed in agent, wherein the organic solvent is selected from dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, C3~C4Alcohol or its Mixture, water is 1 with the volume ratio of organic solvent:3~1:5, stirring and crystallizing, the crystal that will be separated out is separated, at 10~30 DEG C Dry 10~48 hours, obtain the crystal formation B.
The C3~C4Alcohol can be normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol or its mixture.
Preferably, the organic solvent is tetrahydrofuran or Isosorbide-5-Nitrae-dioxane.
Preferably, the water and the volume ratio of organic solvent are 1:4~1:5.
Preferably, the temperature of the crystallization is 10~60 DEG C, more preferably 30~50 DEG C.
Preferably, the time of the crystallization is 1~5 day, more preferably 1~3 day.
Preferably, the consumption of the Sino-German Roger's Wei sodium salt of the suspension is that it is molten in the mixed solvent under recrystallization temperature 2~10 times of Xie Du, more preferably 2~5 times.
Preferably, the dry temperature is 10~20 DEG C.
Preferably, the dry time is 10~24 hours.
The preparation method of above-mentioned crystal formation B employs the crystallization mode of magma, is that (supersaturated solution of sample is had into insoluble Solid presence) stir in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal formation B：The De Luogewei sodium salts can include each of known De Luogewei sodium salts Crystal formation or amorphous article are planted, for example, includes but is not limited to describe method system according to patent document WO2010068253A1 embodiments 1l Standby known De Luogewei sodium salts crystal formation I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiments 1 Known De Luogewei sodium salts amorphous article；The De Luogewei sodium salts can also include De Luogewei sodium salts of the invention Crystal formation A or crystal formation D.
Crystal formation B has following beneficial property：
1. solubility is 2.1mg/mL to crystal formation B in water at room temperature, more known De Luogewei sodium salts monohydrate it is molten Xie Du (solubility is 1.7mg/mL in water at room temperature for it) is high.
2. after crystal formation B is stored 10 days under 80 DEG C of hot and humid illumination conditions of -90%RH-6000lx, under its purity The growth of drop and maximum single miscellaneous content has illustrated its stability more significantly lower than the data of known De Luogewei sodium salt crystal formations I The De Luogewei sodium salt crystal formations I for knowing is good.
3. weight changes of the crystal formation B in 20%-80% RH ranges is only for about 0.5%, relative to known moral It is Roger's Wei sodium salt monohydrate crystal form (its weight change in 20%-80% RH ranges is for about 4.3%), known De Luogewei sodium salt crystal formations I (its weight change in 20%-80% RH ranges is for about 1.1%) is less susceptible to moisture absorption.
4. crystal formation B is rod shaped particles, and the particle than known De Luogewei sodium salts monohydrate is big.
The above-mentioned property of crystal formation B shows：With the known water of De Luogewei sodium salts crystal formation I or known De Luogewei sodium salts one Compound is compared, and crystal formation B of the present invention has the advantages that solubility high, excellent storage stability, to be difficult moisture absorption, granule-morphology good.Its system Agent can have dissolution rate and more preferable bioavilability higher；Mobility of particle is good, the precise in being easy to preparation to produce With topple over, improve batch reproducibility；The good stability of preparation, is suitable for the environmental condition of looser manufacture, storage and transport, Preferably resist because the issuable active constituents of medicine content of the factors such as environment temperature, humidity, illumination is uneven, under purity The problems such as drop, curative effect downside risk and security risk that thus reduction brings.
Purpose of the invention, the present invention provides the n-butanol solvent compound crystal formation C of De Luogewei sodium salts (in the present invention In referred to as " crystal formation C ").
The crystal formation C is the n-butanol solvent compound of De Luogewei sodium salts, and every mole of crystal formation C contains about 1 mole of positive fourth Alcohol, its structural formula is as follows：
Radiated using Cu-K α, the crystal formation C has with the X-ray powder diffraction collection that 2 θ angles are represented in following position Characteristic peak：6.2 ± 0.2 °, 7.9 ± 0.2 °, 12.5 ± 0.2 °, 18.7 ± 0.2 °, 21.3 ± 0.2 ° and 23.8 ± 0.2 °.
Preferably, the crystal formation C has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 6.2±0.2°、7.9±0.2°、12.5±0.2°、12.7±0.2°、12.9±0.2°、18.4±0.2°、18.7±0.2°、 19.1 ± 0.2 °, 21.3 ± 0.2 ° and 23.8 ± 0.2 °.
It is highly preferred that the crystal formation C has feature with the X-ray powder diffraction collection that 2 θ angles are represented in following position Peak and relative intensity：
Without limitation, a representative instance of the crystal formation C has X-ray powder diffraction figure as shown in figure 22.
The FTIR spectrum of the crystal formation C wave number be 3277,2956,2930,2873,1648,1624,1526, 1506th, 1428,1283,1251,1087,981,839 and 743cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation C shows：150 DEG C of sample has 15.17% weightlessness before, is roughly equal to and contains One molecule n-butanol, decomposition temperature is 367 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal formation C shows：It starts fusion and decomposition at 338 DEG C.
The preparation method of the crystal formation C, comprises the following steps：De Luogewei sodium salts are formed into suspension in n-butanol, Stirring and crystallizing, the crystal that will be separated out is separated, dried, and obtains the crystal formation C.
Preferably, the temperature of the crystallization is 10~60 DEG C, more preferably 30~50 DEG C.
Preferably, the time of the crystallization is 12~48 hours, more preferably 12~24 hours.
Preferably, the consumption of the Sino-German Roger's Wei sodium salt of the suspension is its solubility in n-butanol under recrystallization temperature 2~10 times, more preferably 2~5 times.
Preferably, the dry temperature is 10~60 DEG C, more preferably 10~40 DEG C.
Preferably, the dry time is 10~48 hours, more preferably 10~24 hours.
The preparation method of above-mentioned crystal formation C employs the crystallization mode of magma, is that (supersaturated solution of sample is had into insoluble Solid presence) stir in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal formation C, the De Luogewei sodium salts can include each of known De Luogewei sodium salts Crystal formation or amorphous article are planted, for example, includes but is not limited to describe method system according to patent document WO2010068253A1 embodiments 1l Standby known De Luogewei sodium salts crystal formation I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiments 1 Known De Luogewei sodium salts amorphous article；The De Luogewei sodium salts can also include De Luogewei sodium salts of the invention Crystal formation A or crystal formation D.
Crystal formation C has following beneficial property：
1. solubility is 4.6mg/mL, the solubility of more known De Luogewei sodium salts crystal formation I to crystal formation C in water at room temperature (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of more known De Luogewei sodium salts monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high.
2. crystal formation C is placed 4 months in room temperature, the drier of 10%~90%RH of relative humidity, and crystal formation is constant.
The above-mentioned property of crystal formation C shows：With known De Luogewei sodium salts crystal formation I and the known water of De Luogewei sodium salts one Compound is compared, and crystal formation C of the invention has the advantages that solubility is high, excellent storage stability.Preparation can have dissolution rate higher With more preferable bioavilability, and adapt to the environmental condition of looser manufacture, storage and transport, preferably resist due to when Between, humidity etc. is the problems such as the issuable active constituents of medicine content of factor is uneven, purity declines, the treatment that thus reduction brings Effect downside risk and security risk.
Purpose of the invention, the crystal formation D that the present invention provides De Luogewei sodium salts (is referred to as " crystal formation in the present invention D”)。
The crystal formation D is the anhydride of De Luogewei sodium salts, and its structural formula is as follows：
Radiated using Cu-K α, the crystal formation D has with the X-ray powder diffraction collection that 2 θ angles are represented in following position Characteristic peak：6.4 ± 0.2 °, 8.2 ± 0.2 °, 13.0 ± 0.2 °, 15.7 ± 0.2 °, 18.5 ± 0.2 ° and 19.5 ± 0.2 °.
Preferably, the crystal formation D has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 6.4±0.2°、8.2±0.2°、13.0±0.2°、14.5±0.2°、15.7±0.2°、18.5±0.2°、19.5±0.2°、 21.3 ± 0.2 °, 21.8 ± 0.2 °, 25.0 ± 0.2 ° and 27.8 ± 0.2 °.
It is highly preferred that the crystal formation D has feature with the X-ray powder diffraction collection that 2 θ angles are represented in following position Peak and relative intensity：
Without limitation, a representative instance of the crystal formation D has X-ray powder diffraction figure as shown in figure 27.
The FTIR spectrum of the crystal formation D wave number be 2922,1636,1621,1531,1504,1425,1317, 1280th, 1254,1198,1110,964,858 and 744cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation D shows：Sample decomposition temperature is about 349 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal formation D shows：It starts fusion and decomposition at 345 DEG C.
The preparation method of the crystal formation D, using any one in following preparation method：
(1) by the n-butanol solvent compound crystal formation C of De Luogewei sodium salts with 5~20 DEG C/min of heating rate from room temperature 150 DEG C of desolventizing temperature is warming up to, 15~35 minutes is kept at 150 DEG C to solvent is sloughed completely, then with 5~20 DEG C/minute The cooldown rate of clock is cooled to room temperature, obtains the crystal formation D.
Preferably, the time of the holding is 20~35 minutes；More preferably 20~30 minutes.
Preferably, the heating rate is 5~10 DEG C/min.
Preferably, the cooldown rate is 10~20 DEG C/min.
(2) the n-butanol solvent compound crystal formation C of De Luogewei sodium salts is placed 25~40 in 130~150 DEG C of environment Minute to sloughing solvent completely, then it is placed directly within room temperature, obtains the crystal formation D.
Preferably, the temperature of the environment is 140~150 DEG C.
Preferably, the time of the placement is 25~35 minutes.
The preparation method of above-mentioned crystal formation D employs the crystallization mode of high temperature desolventizing.
Crystal formation D has following beneficial property：
1. solubility is 4.2mg/mL, the solubility of more known De Luogewei sodium salts crystal formation I to crystal formation D in water at room temperature (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of more known De Luogewei sodium salts monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high.
2. after crystal formation D is stored 10 days under 80 DEG C of hot and humid illumination conditions of -90%RH-6000lx, under its purity The growth of drop and maximum single miscellaneous content has illustrated its stability more significantly lower than the data of known De Luogewei sodium salt crystal formations I The De Luogewei sodium salt crystal formations I for knowing is good.
3. crystal formation D weight changes in 20%-80% RH ranges are only for about 0.1%, relative to known moral sieve Lattice Wei sodium salt crystal formation I (its weight change in 20%-80% RH ranges is for about 1.1%) and known De Luogewei sodium Salt monohydrate (its weight change in 20%-80% RH ranges is for about 4.3%) is less susceptible to moisture absorption.
4. crystal formation D is placed 4 months in room temperature, the drier of 10%~90%RH of relative humidity, and crystal formation is constant.
The above-mentioned property of crystal formation D shows：With known De Luogewei sodium salts crystal formation I and the known water of De Luogewei sodium salts one Compound is compared, and crystal formation D of the invention has the advantages that solubility is high, is difficult moisture absorption, excellent storage stability.The solid system of disclosure satisfy that The use requirement of agent, machinability is good, and batch reproducibility is good, and preparation has dissolution rate and more preferable bioavilability higher, And adapt to the environmental condition of looser manufacture, storage and transport, preferably resist due to the factors such as time, humidity there may be Active constituents of medicine content it is uneven, the problems such as purity declines, curative effect downside risk and security risk that thus reduction brings.
Purpose of the invention, the present invention provides the trifluoroethanol solvate crystal formation E of De Luogewei sodium salts (in this hair In bright referred to as " crystal formation E ").
The crystal formation E is the trifluoroethanol solvate of De Luogewei sodium salts, and every mole of crystal formation E contains about 1 mole Trifluoroethanol, its structural formula is as follows：
Radiated using Cu-K α, the crystal formation E has with the X-ray powder diffraction collection that 2 θ angles are represented in following position Characteristic peak：6.4 ± 0.2 °, 6.9 ± 0.2 °, 11.2 ± 0.2 °, 11.7 ± 0.2 °, 19.2 ± 0.2 ° and 20.9 ± 0.2 °.
Preferably, the crystal formation E has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 6.4 ± 0.2 °, 6.9 ± 0.2 °, 11.2 ± 0.2 °, 11.7 ± 0.2 °, 19.2 ± 0.2 °, 20.9 ± 0.2 °, 23.0 ± 0.2 ° and 27.9±0.2°。
It is highly preferred that the crystal formation E has feature with the X-ray powder diffraction collection that 2 θ angles are represented in following position Peak and relative intensity：
Without limitation, a representative instance of the crystal formation E has the X-ray powder diffraction figure as shown in 33.
The FTIR spectrum of the crystal formation E wave number be 3419,3076,1641,1536,1503,1424,1321, 1282nd, 1258,1069,1023,963,763 and 722cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) collection of illustrative plates of the crystal formation E shows：There is 15.1% weightlessness before 150 DEG C of sample, be roughly equal to containing one point Sub- trifluoroethanol, is trifluoroethanol solvate；Decomposition temperature is 367 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal formation E shows that it is starting fusion and decomposition at 337 DEG C.
The preparation method of the crystal formation E, using any one in following preparation method：
(1) De Luogewei sodium salts are formed into solution in the mixed solvent of trifluoroethanol or trifluoroethanol with organic solvent, The organic solvent is selected from C1~C4Alcohol, C4~C5Ester, acetonitrile or its mixture, then the crystallization that volatilizees naturally, obtain the crystal formation E.
The C1~C4Alcohol can be methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol；The C4~C5Ester Can be ethyl acetate or isopropyl acetate.
Preferably, the organic solvent is selected from ethanol, ethyl acetate or acetonitrile.
Preferably, the trifluoroethanol and the volume ratio of organic solvent are 1:1~4:1, more preferably 1:1~2:1.
Preferably, the operation temperature of the preparation method is 20~60 DEG C, more preferably 30~50 DEG C.
Preferably, the time of the crystallization is 1~5 day, more preferably 1~3 day.
Preferably, the concentration of the De Luogewei sodium salt solutions is that De Luogewei sodium salts are molten in trifluoroethanol or the mixing 0.2~1 times of solubility in agent, more preferably preferably 0.5~1 times, 0.8~1 times.
The preparation method (1) of above-mentioned crystal formation E employs the crystallization mode of nature volatilization crystallization.Concrete operations are：By sample Settled solution be placed in open glass bottle, open or add a cover punching, volatilization naturally removes solvent, acquisition crystal.
(2) to anti-solvent is added in the trifluoroethanol solution of De Luogewei sodium salts, wherein the anti-solvent is selected from C1~C4 Alcohol, C4~C5Ester, isopropyl ether, acetonitrile, toluene or its mixture, stirring and crystallizing, the crystal that will be separated out are separated, dried, and obtain described Crystal formation E.
The C1~C4Alcohol can be methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol；The C4~C5Ester Can be ethyl acetate or isopropyl acetate.
Preferably, the anti-solvent is selected from ethanol, ethyl acetate or acetonitrile.
Preferably, the volume of the anti-solvent is 5~20 times, more preferably 10~15 times of trifluoroethanol volume.
Preferably, the temperature of the crystallization is 10~60 DEG C, more preferably room temperature.
Preferably, the time of the crystallization is 1~24 hour, more preferably 1~5 hour.
Preferably, the concentration of the De Luogewei sodium salt solutions be recrystallization temperature under De Luogewei sodium salts in trifluoroethanol 0.2~1 times of solubility, more preferably 0.5~1 times.
Preferably, the dry temperature is 5~30 DEG C, more preferably 20~30 DEG C.
Preferably, the dry time is 10~48 hours, more preferably 10~24 hours.
The preparation method (2) of above-mentioned crystal formation E employ anti-solvent recrystallization crystallization mode, be sample is dissolved in it is good molten In agent, then appropriate anti-solvent is added, the dissolubility difference using sample in different solvents separates out crystal.
In the preparation method of above-mentioned crystal formation E, the De Luogewei sodium salts can include each of known De Luogewei sodium salts Crystal formation or amorphous article are planted, for example, includes but is not limited to describe method system according to patent document WO2010068253A1 embodiments 1l Standby known De Luogewei sodium salts crystal formation I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiments 1 Known De Luogewei sodium salts it is unformedThing；The De Luogewei sodium salts can also include De Luogewei sodium salts of the invention Crystal formation A or crystal formation D.
Crystal formation E has following beneficial property：
1. solubility is 3.7mg/mL, the solubility of more known De Luogewei sodium salts crystal formation I to crystal formation E in water at room temperature (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of more known De Luogewei sodium salts monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high, illustrate that crystal formation E of the present invention has solubility higher.
2. crystal formation E is placed 4 months in room temperature, the drier of 10%~90%RH of relative humidity, and crystal formation is constant.
The above-mentioned property of crystal formation E shows：With known De Luogewei sodium salts crystal formation I and the known water of De Luogewei sodium salts one Compound is compared, and crystal formation D of the invention has the advantages that solubility is high, excellent storage stability.Preparation have dissolution rate higher and More preferable bioavilability, and adapt to the environmental condition of looser manufacture, storage and transport, preferably resist due to the time, The problems such as issuable active constituents of medicine content of the factors such as humidity is uneven, purity declines, the curative effect that thus reduction brings Downside risk and security risk.
In crystal formation A, crystal formation B, crystal formation C, the preparation method of crystal formation D or crystal formation E of the above-mentioned Roger's Wei sodium salt of the present invention：
" room temperature " refers to about 10~30 DEG C of temperature.
" stirring ", can be completed, agitating mode such as magnetic agitation, mechanical agitation using the conventional method of this area It it is 50~1800 revs/min, preferably 300~900 revs/min Deng, mixing speed.
" separation ", can be completed using the ordinary skill in the art, for example, filter or be centrifuged.The filtering is usually Suction filtration is carried out with the pressure less than atmospheric pressure at ambient temperature, preferably pressure is less than 0.09MPa.The concrete operations of the centrifugation For：The sample for being intended to separate is placed in centrifuge tube, is centrifuged with 6000 revs/min of speed, until solid is all sink to centrifugation Bottom of the tube.The crystal obtained through " separation " can be washed further, washing solvent used preferably with crystal preparation method In solvent used it is identical, the consumption of cleaning solvent is generally 0.3~1 times of solvent volume used in crystal preparation method.
" anhydride " refers to that sample contains not more than 1.5% (weight ratio) or not more than 1.0% (weight through TGA detections Amount ratio) water.
The present invention is solved by providing crystal formation A, crystal formation B, crystal formation C, crystal formation D and the crystal formation E of new De Luogewei sodium salts The problem that prior art crystal formation is present, the novel crystal forms are with known crystal formation compared with least one or more of beneficial property Matter, for example：Solubility higher, dissolution rate, be not susceptible to polymorphic inversion and/or dehydration, calorifics and good mechanical stability, Agent of low hygroscopicity, more preferable mobility, compressibility and good, the low-residual solvent of apparent density, storage stability etc..
In the present invention, " crystal " or " crystal formation " refers to characterizing what is confirmed by shown X-ray diffractogram.This area skill Art personnel are it is understood that experimental error therein depends on preparation and the purity of sample of the condition, sample of instrument.Particularly, As well known to those skilled in the art, X-ray diffractogram would generally be changed with the condition of instrument.In particular It is that the relative intensity of X-ray diffractogram is likely to change with the change of experiment condition, so the order of peak intensity can not be made It is unique or deciding factor.In addition, the experimental error of peak angle degree is generally 5% or less, the error of these angles also should It is considered into, allows generally for ± 0.2 error.Further, since the influence of the empirical factor such as height of specimen, can cause peak angle The overall offset of degree, allows generally for certain skew.Thus, it will be appreciated by persons skilled in the art that it is any with this The same or analogous crystal formation of characteristic peak of invention collection of illustrative plates is belonged within scope of the invention.
" crystal " of the present invention or " crystal formation " are pure, single, and any other crystal formation is not mixed substantially.The present invention In, " not having substantially " refers to that this crystal formation contains other crystal formations less than 20% (weight) when novel crystal forms are used to refer to, especially few In other crystal formations of 10% (weight), more refer to other crystal formations less than 5% (weight), more refer to other crystalline substances less than 1% (weight) Type.
Additionally, the present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition includes treatment and/or prevention effective dose Active constituents of medicine be selected from the crystal formation A of De Luogewei sodium salts of the invention, crystal formation B, crystal formation C, crystal formation D, crystal formation E or according to Crystal formation A, crystal formation B, crystal formation C, crystal formation D, the crystal formation E of the De Luogewei sodium salts of the invention that preparation method of the present invention is obtained, and At least one pharmaceutically acceptable carrier or auxiliary agent.Described pharmaceutical composition can also include De Luogewei sodium salts other can Medicinal crystal formation or the crystal formation of other officinal salts of amorphous article or De Luogewei or its amorphous article.Optionally, the medicine Compositions include one or more other active constituents of medicine, including but not limited to other antiviral drugs, for example, have There are the inverase such as RTI and/or protease inhibitors of different mechanism of action.
Described pharmaceutical composition can be made appropriate pharmaceutical dosage forms, can be administered orally or parenterally.It is suitable to The pharmaceutical preparation of oral administration, solid oral dosage form for example including tablet, granule, powder, pill, powder, capsule etc., liquid Body peroral dosage form for example including solution, syrup, supensoid agent, emulsion agent etc., De Luogewei of the invention in the supensoid agent The crystal formation of sodium salt remains solid form.Be suitable to the pharmaceutical preparation of parenteral, such as including intravenous drip preparations, muscle or Subcutaneous injection agent, the suppository of per rectum administration, the spray of intravaginal administration, paste, the suction preparation or part of intranasal administration The transdermal patch form of administration.Formula may be adapted to quick release, sustained release or the regulation release of active component.
In solid oral dosage form, acceptable carrier or auxiliary agent are included but is not limited in described pharmaceutical composition Chinese pharmacology： It is diluent, such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, calcium phosphate dibasic anhydrous, tricalcium phosphate, sweet Dew alcohol, sorbierite, sugar etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, polyethylene glycol, copolyvidone etc.；Disintegrant, such as starch, sodium carboxymethyl starch, hydroxyacetic acid form sediment Powder sodium, pregelatinized starch, PVPP, Ac-Di-Sol, cataloid etc.；Lubricant, such as it is stearic Acid, magnesium stearate, zinc stearate, Sodium Benzoate, sodium acetate etc.；Glidant, such as cataloid etc.；Compound is formed Agent, such as cyclodextrin and resin of various ranks；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyl Propyl methocel, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc..Other are available can pharmaceutically to connect The carrier received including but not limited to film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier, preservative, antioxidant etc.. In liquid oral dosage form, acceptable carrier or auxiliary agent include that aqueous, oiliness or alcohols are molten in described pharmaceutical composition Chinese pharmacology The solvent of liquid such as sterilized water, normal saline solution, glucose solution, mannitol solution, vegetable oil, cod-liver oil, ethanol, third Alcohol, glycerine etc..Further, it is also possible to use the carriers such as polyethylene glycol, polypropylene glycol.Be adapted to parenteral in the case of, water or Non-aqueous sterile solution injection can contain buffer, antioxidant, bacteriostatic agent and can make the pharmaceutical composition and blood Isotonic solute, water or non-aqueous sterile suspensions can contain suspending agent and thickener.Each carrier or auxiliary agent must be It is acceptable, can be compatible with the other compositions in formula and harmless for sufferer.
Described pharmaceutical composition can use well known to a person skilled in the art method to prepare.Prepare pharmaceutical composition When, the crystal formation A of De Luogewei sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or crystal formation E can pharmaceutically be connect with one or more The carrier or auxiliary agent received are mixed, and optionally, are mixed with one or more other active constituents of medicine.Solid pharmaceutical preparation can be with Prepared by techniques such as mixing, granulations.Liquid preparation can be prepared by techniques such as dissolving, dispersion, emulsifications.
The crystal formation A of De Luogewei sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or crystal formation E have to the integrase of virus Significant inhibitory action, as the integration enzyme level of retrovirus (including HIV-1, HIV-2, HTLV-1, SIV-1, FIV-1) Agent, particularly for preparation treatment and/or the medicine of pre- preventing HIV infection.
Additionally, the present invention provides a kind of method treated and/or prevent HIV-1 infection, methods described includes giving needs Patient's treatment and/or the crystal formation A selected from De Luogewei sodium salts of the invention of prevention effective dose, crystal formation B, crystal formation C, crystal formation D, The foregoing pharmaceutical combination of crystal formation E or the crystal formation A containing De Luogewei sodium salts of the present invention, crystal formation B, crystal formation C, crystal formation D or crystal formation E Thing.Different dosage is used according to the difference of medication, patient age, body weight and the state of an illness.Generally in the feelings being administered orally Under condition, each adult gives about 0.1mg~1000mg daily；In the case of parenteral, each adult gives about daily 0.05mg~500mg.
Brief description of the drawings
Fig. 1 is the XRPD figures of known De Luogewei sodium salts crystal formation I prepared by preparation example 1.
Fig. 2 is the PLM figures of known Roger's Wei sodium salt crystal formation I prepared by preparation example 1.
Fig. 3 is the adsorption isothermal curve figure of known De Luogewei sodium salts crystal formation I prepared by preparation example 1.
Fig. 4 is the IR figures of known De Luogewei sodium salts crystal formation I prepared by preparation example 1.
Fig. 5 is the XRPD figures of known De Luogewei sodium salts amorphous article prepared by preparation example 2.
Fig. 6 is the XRPD figures of known De Luogewei sodium salts monohydrate prepared by preparation example 3.
Fig. 7 is the PLM figures of known De Luogewei sodium salts monohydrate prepared by preparation example 3.
Fig. 8 is the adsorption isothermal curve figure of known De Luogewei sodium salts monohydrate prepared by preparation example 3.
Fig. 9 is the IR figures of known De Luogewei sodium salts monohydrate prepared by preparation example 3.
Figure 10 is the XRPD figures of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 11 is the PLM figures of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 12 is the DSC figures of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 13 is the TGA figures of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 14 is the adsorption isothermal curve figure of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 15 is the IR figures of the crystal formation A of De Luogewei sodium salts of the present invention.
Figure 16 is the XRPD figures of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 17 is the PLM figures of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 18 is the DSC figures of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 19 is the TGA figures of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 20 is the adsorption isothermal curve figure of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 21 is the IR figures of the crystal formation B of De Luogewei sodium salts of the present invention.
Figure 22 is the XRPD figures of the crystal formation C of De Luogewei sodium salts of the present invention.
Figure 23 is the PLM figures of the crystal formation C of De Luogewei sodium salts of the present invention.
Figure 24 is the DSC figures of the crystal formation C of De Luogewei sodium salts of the present invention.
Figure 25 is the TGA figures of the crystal formation C of De Luogewei sodium salts of the present invention.
Figure 26 is the IR figures of the crystal formation C of De Luogewei sodium salts of the present invention.
Figure 27 is the XRPD figures of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 28 is the PLM figures of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 29 is the DSC figures of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 30 is the TGA figures of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 31 is the adsorption isothermal curve figure of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 32 is the IR figures of the crystal formation D of De Luogewei sodium salts of the present invention.
Figure 33 is the XRPD figures of the crystal formation E of De Luogewei sodium salts of the present invention.
Figure 34 is the PLM figures of the crystal formation E of De Luogewei sodium salts of the present invention.
Figure 35 is the DSC figures of the crystal formation E of De Luogewei sodium salts of the present invention.
Figure 36 is the TGA figures of the crystal formation E of De Luogewei sodium salts of the present invention.
Figure 37 is the IR figures of the crystal formation E of De Luogewei sodium salts of the present invention.
Specific embodiment
With further reference to following examples, the embodiment describes the preparation of crystal formation of the invention in detail and uses the present invention Method.It will be apparent for a person skilled in the art that for many changes of both material and method this hair can not departed from Implement in the case of bright scope.
Instrument and method used by gathered data：
X-ray powder diffraction (XPRD)：The instrument for being used is Bruker D8Advance diffractometer, is adopted With the Ka X-rays that copper target wavelength is 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is calibrated using the preceding standard items (generally corundum) carried with instrument.Sample is at ambient temperature Test, is placed on areflexia plate the sample of detection is needed.Detailed testing conditions are as follows, angular range：3-40 ° of 2 θ, step-length： 0.02 ° of 2 θ, speed：0.2 second/step.
Polarization microscope (PLM) figure is picked up from XP-500E polarization microscopes (the Shanghai limited public affairs of rectangular optical instrument Department).Take a small amount of powder sample to be placed on slide, a small amount of mineral oil is added dropwise with preferably dispersion powders sample, covered, Then sample is placed on the objective table of XP-500E polarization microscopes, selects the shape of suitable multiplication factor observing samples Looks are simultaneously taken pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample for generally taking 1~10mg is positioned in aluminium dish, with 10 DEG C/min programming rate sample is risen to 375 DEG C or 400 DEG C from 0 DEG C under the protection of drying nitrogen in 40mL/ minutes.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500TGA, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample for generally taking 5~15mg is positioned in platinum crucible, is adopted With segmentation high resolution detection mode, with 10 DEG C/min of programming rate under the protection of drying nitrogen in 40mL/ minutes by sample 400 DEG C or 450 DEG C are risen to from room temperature.
Adsorption isothermal curve：Data are picked up from TA Instruments Q5000TGA, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample for generally taking 1~10mg is positioned in platinum crucible, TA Weight change of the software records sample in relative humidity from 0% to 80% to 0% in change procedure.According to the specific feelings of sample Condition, also can use different absorption and De contamination step to sample.
Infrared spectrum analysis (IR) data are picked up from BrukerTensor 27, instrument control software and DAS All it is OPUS, ATR equipment is generally used, in 600-4000cm-1In the range of gather infrared absorption spectroscopy, sample and blank background Sweep time is 16 seconds, and instrumental resolution is 4cm-1。
High-efficient liquid phase analysis (HPLC) data are picked up from Agilent 1260, and instrument control software is Agilent chemistry works Stand B.04 version online, and analysis software is Agilent chem workstations B.04 version offline.Using C18 chromatographic columns, 250mm*4.6mm, 35 DEG C of column temperature, wavelength 254nm, flow velocity 0.7mL/ minutes, the μ L of sample size 20, run time 30 minutes.Flowing Phase A is potassium dihydrogen phosphate containing 0.01mol/L, and Mobile phase B is acetonitrile, mobile phase A:Mobile phase B=55:45.
Various reagents used are commercially available unless otherwise instructed in embodiment.
Temperature in embodiment is room temperature unless otherwise instructed.
In embodiment, the ratio of component is volume ratio unless otherwise instructed in mixed solvent.
Ultrasound procedure in embodiment can promote sample to dissolve, and equipment is ultrasonic cleaner, is carried out under 40kHz power 5 minutes.
Preparation example 1Prepare known De Luogewei sodium salt crystal formations I
The side that known De Luogewei sodium salts crystal formation I can be described according to patent document WO2010/068253A1 embodiments 1l Method is prepared.
Specifically preparation method is：12.0g De Luogewei are dissolved in 36mL ethanol by heating, will at 80 DEG C The NaOH aqueous solution of 14.5mL 2N is added in the solution, and the solution is gradually cooling into room temperature, filtering, is washed with 50mL ethanol Wash and 50 DEG C of dryings, obtain De Luogewei sodium salts.
XRPD figures are shown in the crystal formation I mono- of Fig. 1, display and De Luogewei sodium salts disclosed in patent document WO2010/068253A1 Cause.
PLM figures are shown in Fig. 2, are shown as smaller, rod-shpaed particle.
Adsorption isothermal curve figure is shown in Fig. 3, display：Weight change is 1.1% in 20%-80% RH ranges.
IR figures are shown in Fig. 4, show consistent with the crystal formation I of De Luogewei sodium salts disclosed in patent document WO2010/068253A1.
Preparation example 2Prepare known De Luogewei sodium salt amorphous articles
Known De Luogewei sodium salts amorphous article refers to 3.1 sides of patent document WO2013/038407A1 embodiments 1 Method I is prepared.
Specially：The De Luogewei sodium salt crystal formation I of the preparation of 40mg preparation examples 1 are weighed, with ball mill with 200 revs/min Speed ball milling 200 minutes, that is, obtain De Luogewei sodium salt amorphous articles.
XRPD figures are shown in Fig. 5, show without characteristic peak, are amorphous article.
Preparation example 3Prepare known De Luogewei sodium salt monohydrates
What known De Luogewei sodium salts monohydrate can be described according to patent document WO2010/068253A1 embodiments 1m Method is prepared.
Specifically preparation method is：10g De Luogewei sodium salts are dissolved in 200mL tetrahydrofurans-water (4 at 30 DEG C:1) solution In, add the 2N NaOH aqueous solution of 12mL.Mixture is stirred at room temperature 2 hours, is filtered, filter cake 100mL tetrahydrochysene furans Mutter-water (4:1) solution and 100mL tetrahydrofurans are washed, and 85 DEG C of dryings obtain De Luogewei sodium salt monohydrates.
XRPD figures are shown in the monohydrate of Fig. 6, display and De Luogewei sodium salts disclosed in patent document WO2010/068253A1 Crystal formation is consistent.
PLM figures are shown in Fig. 7, are shown as little particle.
Adsorption isothermal curve figure is shown in Fig. 8, display：Weight change is 4.3% in 20%-80% RH ranges.
IR figures are shown in Fig. 9, and display is brilliant with the monohydrate of De Luogewei sodium salts disclosed in patent document WO2010/068253A1 Type is consistent.
Embodiment 1
The known De Luogewei sodium salts crystal formation I of the preparation of 40mg preparation examples 1 is weighed, 5.0mL water is added:Acetonitrile (4:1) Mixed solvent formed suspension (in the suspension consumption of known De Luogewei sodium salts crystal formation I under recrystallization temperature its in institute State solubility in mixed solvent 2 times), this suspension is stirred 5 days at 60 DEG C, filtering, filter cake 2.0mL water:Acetonitrile (4:1) Mixed solvent washing, 40 DEG C be vacuum dried 10 hours, obtain 38.4mg De Luogewei sodium salt crystal formations A.
XRPD figures are shown in Figure 10.
PLM figures are shown in Figure 11, display：It is smaller, irregular particle.
DSC figures are shown in Figure 12.
TGA figures are shown in Figure 13, display：It is anhydride weightless 1.0% before 150 DEG C.
Adsorption isothermal curve figure is shown in Figure 14, display：Weight change is 1.0% in 20%-80% RH ranges.
IR figures are shown in Figure 15.
Embodiment 2
The known De Luogewei sodium salts crystal formation I of the preparation of 100mg preparation examples 1 is weighed, 5.0mL water is added:1,4- dioxies six Ring (5:1) mixed solvent forms suspension, and (consumption of known De Luogewei sodium salts crystal formation I is recrystallization temperature in the suspension It is lower its 5 times of solubility in the mixed solvent), this suspension is stirred 6 days at 50 DEG C, filtering, filter cake 1.5mL water: 1,4- dioxane (5:1) mixed solvent washing, 30 DEG C of dryings 15 hours obtain 92.1mg De Luogewei sodium salt crystal formations A.
Embodiment 3
The known De Luogewei sodium salts amorphous article of the preparation of 90mg preparation examples 2 is weighed, 5.0mL water is added:Acetone (4.5: 1) mixed solvent forms suspension, and (consumption of known De Luogewei sodium salts amorphous article is under recrystallization temperature in the suspension It is 4.5 times of solubility in the mixed solvent), this suspension to be stirred 8 days at 40 DEG C, 3.5mL water is used in filtering:Acetone (4.5:1) mixed solvent washing, 10 DEG C of dryings 24 hours obtain 80.9mg De Luogewei sodium salt crystal formations A.
Embodiment 4
The known De Luogewei sodium salts amorphous article of the preparation of 100mg preparation examples 2 is weighed, 5.0mL water is added:Butanone (3: 1) mixed solvent forms suspension, and (consumption of known De Luogewei sodium salts amorphous article is under recrystallization temperature in the suspension It is 10 times of solubility in the mixed solvent), this suspension is stirred 14 days at 10 DEG C, filtering, filter cake 5.0mL water: Butanone (3:1) mixed solvent washing, 60 DEG C of dryings 48 hours obtain 17.4mg De Luogewei sodium salt crystal formations A.
There is sample prepared by embodiment 2~4 XRPD same or analogous with the sample of embodiment 1 figures, IR to scheme, PLM schemes, DSC figures, TGA figures and adsorption isothermal curve figure (not shown).Illustrate that the sample of embodiment 2~4 and the sample of embodiment 1 are identical things Matter.
Embodiment 5
The known De Luogewei sodium salts crystal formation I of the preparation of 60mg preparation examples 1 is weighed, 5.0mL water is added:Tetrahydrofuran (1: 4) mixed solvent formed suspension (in the suspension consumption of known De Luogewei sodium salts crystal formation I be under recrystallization temperature its 2 times of solubility in the mixed solvent), this suspension is stirred 1 day at 60 DEG C, filtering, filter cake 2.0mL water:Tetrahydrochysene Furans (1:4) mixed solvent washing, 10 DEG C are vacuum dried 24 hours, obtain the crystal formation B of 58.7mg De Luogewei sodium salts.
XRPD figures are shown in Figure 16.
PLM figures are shown in Figure 17, display：It is rod shaped particles.
DSC figures are shown in Figure 18.
TGA figures are shown in Figure 19, display：Weightless 6.2% (water containing surface 2.0%), is roughly equal to containing a molecular water before 150 DEG C.
Adsorption isothermal curve figure is shown in Figure 20, display：Weight change is 0.5%, explanation in 20%-80% RH ranges It is difficult moisture absorption.
IR figures are shown in Figure 21.
Embodiment 6
The crystal formation A of 150mg De Luogewei sodium salts of the invention is weighed, 5.0mL water is added:1,4- dioxane (1:5) Mixed solvent formed suspension (in the suspension consumption of De Luogewei sodium salts crystal formation A of the invention be recrystallization temperature under its 3 times of solubility in the mixed solvent), this suspension is stirred 2 days at 50 DEG C, filtering, filter cake 4.0mL water:1,4- bis- The ring (1 of oxygen six:5) mixed solvent washing, 15 DEG C of dryings 18 hours obtain the crystal formation B of 150.0mg De Luogewei sodium salts.
Embodiment 7
The crystal formation D of 90mg De Luogewei sodium salts of the invention is weighed, 5.0mL water is added:Normal propyl alcohol (1:4.5) mixing is molten Dosage form into suspension (in the suspension consumption of De Luogewei sodium salts crystal formation D of the invention be under recrystallization temperature its described mixed 4 times of solubility in bonding solvent), this suspension is stirred 3 days at 30 DEG C, filtering, filter cake 1.5mL water:Normal propyl alcohol (1:4.5) Mixed solvent washing, 16 DEG C of dryings 14 hours obtain the crystal formation B of 86.0mg De Luogewei sodium salts.
Embodiment 8
The known De Luogewei sodium salts crystal formation I of the preparation of 30mg preparation examples 1 is weighed, 5.0mL water is added:Dimethyl sulfoxide (1: 3) mixed solvent formed suspension (in the suspension consumption of known De Luogewei sodium salts crystal formation I be under recrystallization temperature its 5 times of solubility in the mixed solvent), this suspension is stirred 4 days at 20 DEG C, filtering, filter cake 3.0mL water:Diformazan Sulfoxide (1:3) mixed solvent washing, 18 DEG C of dryings 12 hours obtain the crystal formation B of 28.0mg De Luogewei sodium salts.
Embodiment 9
The known De Luogewei sodium salts amorphous article of the preparation of 300mg preparation examples 2 is weighed, 5.0mL water is added:N-butanol (1:4.2) mixed solvent forms suspension, and (consumption of known De Luogewei sodium salts amorphous article is crystallization in the suspension At a temperature of its 10 times of solubility in the mixed solvent), this suspension is stirred 5 days at 10 DEG C, filtering, filter cake is used 1.5mL water:N-butanol (1:4.2) mixed solvent washing, 20 DEG C of dryings 10 hours obtain 270.8mg De Luogewei sodium salts Crystal formation B.
There is sample prepared by embodiment 6~9 XRPD same or analogous with the sample of embodiment 5 figures, IR to scheme, PLM schemes, DSC figures, TGA figures and adsorption isothermal curve figure (not shown).Illustrate that the sample of embodiment 6~9 and the sample of embodiment 5 are identical things Matter.
Embodiment 10
The known De Luogewei sodium salts crystal formation I of the preparation of 50mg preparation examples 1 is weighed, addition 5.0mL n-butanols are formed and are suspended Liquid (in the suspension consumption of known De Luogewei sodium salts crystal formation I be under recrystallization temperature its 2 times of solubility in n-butanol), This suspension is stirred 12 hours at 50 DEG C, filtering, filter cake is washed with 1.5mL n-butanols, 40 DEG C are vacuum dried 10 hours, obtain The crystal formation C of 54.7mg De Luogewei sodium salts.
XRPD figures are shown in Figure 22.
PLM figures are shown in Figure 23, are shown as little particle.
DSC figures are shown in Figure 24.
TGA figures are shown in Figure 25, display：Weightless 15.2% before 150 DEG C, it is roughly equal to containing a molecule n-butanol.
IR figures are shown in Figure 26.
Embodiment 11
The known De Luogewei sodium salts crystal formation I of the preparation of 75mg preparation examples 1 is weighed, addition 5.0mL n-butanols are formed and are suspended Liquid (in the suspension consumption of known De Luogewei sodium salts crystal formation I be recrystallization temperature under its in n-butanol solubility 3 Times), this suspension being stirred 18 hours at 40 DEG C, filtering, filter cake washs with 3.0mL n-butanols, 35 DEG C of dryings 13 hours, obtains The crystal formation C of 80.3mg De Luogewei sodium salts.
Embodiment 12
The crystal formation A of 125mg De Luogewei sodium salts of the invention is weighed, addition 5.0mL n-butanols form suspension (suspension In liquid the consumption of the crystal formation A of De Luogewei sodium salts of the invention be under recrystallization temperature its 5 times of solubility in n-butanol), 30 DEG C stirring 24 hours, filtering, filter cake washs with 3.0mL n-butanols, 10 DEG C of dryings 48 hours, obtains 129.5mg De Luogewei sodium The crystal formation C of salt.
Embodiment 13
The crystal formation D of 25mg De Luogewei sodium salts of the invention is weighed, addition 5.0mL n-butanols form suspension (suspension In liquid the consumption of De Luogewei sodium salts crystal formation D of the invention be under recrystallization temperature its 2 times of solubility in n-butanol), by this Suspension is stirred 13 hours at 60 DEG C, filtering, and filter cake washs with 3.0mL n-butanols, 18 DEG C of dryings 16 hours, obtains 25.3mg morals The crystal formation C of Roger's Wei sodium salt.
Embodiment 14
The known De Luogewei sodium salts amorphous article of the preparation of 250mg preparation examples 2 is weighed, 5.0mL n-butanol solvents are added (consumption of known De Luogewei sodium salts amorphous article is that it is molten in n-butanol under recrystallization temperature in the suspension to form suspension 10 times of Xie Du), this suspension is stirred 48 hours at 10 DEG C, filtering, filter cake is washed with 3.0mL n-butanols, 60 DEG C of dryings 28 Hour, obtain the crystal formation C of 244.7mg De Luogewei sodium salts.
Sample prepared by embodiment 11~14 has XRPD same or analogous with the sample of embodiment 10 figures, IR figures, PLM Figure, DSC figures and TGA figure (not shown).Illustrate that the sample of embodiment 11~14 and the sample of embodiment 10 are identical materials.
Embodiment 15
The crystal formation C of 20mg De Luogewei sodium salts prepared by embodiment 10 with 10 DEG C/min from room temperature to 150 DEG C, 30 minutes are kept at 150 DEG C to solvent is sloughed completely, then room temperature is cooled to 10 DEG C/min, that is, obtains 16.9mg moral sieve The crystal formation D of lattice Wei sodium salt.
XRPD figures are shown in Figure 27.
PLM figures are shown in Figure 28, display：It is little particle.
DSC figures are shown in Figure 29.
TGA figures are shown in Figure 30.
Adsorption isothermal curve figure is shown in Figure 31, display：Weight change is 0.06% in 20%~80% RH range.
IR figures are shown in Figure 32.
Embodiment 16
The crystal formation C of 30mg De Luogewei sodium salts prepared by embodiment 10 is warming up to 150 DEG C with 8 DEG C/min, at 150 DEG C Kept for 25 minutes to solvent is sloughed completely, be then cooled to room temperature with 15 DEG C/min, that is, obtain 25.4mg De Luogewei sodium salts Crystal formation D.
Embodiment 17
The crystal formation C of 50mg De Luogewei sodium salts prepared by embodiment 10 is warming up to 150 DEG C with 5 DEG C/min, at 150 DEG C Kept for 20 minutes to solvent is sloughed completely, be then cooled to room temperature with 20 DEG C/min, that is, obtain 42.4mg De Luogewei sodium salts Crystal formation D.
Embodiment 18
The crystal formation C of 28mg De Luogewei sodium salts prepared by embodiment 10 is warming up to 150 DEG C with 15 DEG C/min, at 150 DEG C Kept for 33 minutes to solvent is sloughed completely, be then cooled to room temperature with 8 DEG C/min, that is, obtain 23.8mg De Luogewei sodium salts Crystal formation D.
Embodiment 19
The crystal formation C of 26mg De Luogewei sodium salts prepared by embodiment 10 is warming up to 150 DEG C with 20 DEG C/min, at 150 DEG C Kept for 35 minutes to solvent is sloughed completely, be then cooled to room temperature with 5 DEG C/min, that is, obtain 22.1mg De Luogewei sodium salts Crystal formation D.
Embodiment 20
The crystal formation C of 30mg De Luogewei sodium salts prepared by embodiment 10 is put into 140 DEG C of baking ovens, is kept for 35 minutes to complete It is complete to slough solvent, take out room temperature and place, that is, obtain the crystal formation D of 25.4mg De Luogewei sodium salts.
Embodiment 21
The crystal formation C of 50mg De Luogewei sodium salts prepared by embodiment 10 is put into 150 DEG C of baking ovens, and 25 are kept at 150 DEG C Minute, to solvent is sloughed completely, takes out room temperature and places, that is, obtain the crystal formation D of 42.4mg De Luogewei sodium salts.
Embodiment 22
The crystal formation C of 45mg De Luogewei sodium salts prepared by embodiment 10 is put into 145 DEG C of baking ovens, and 30 are kept at 145 DEG C Minute, to solvent is sloughed completely, takes out room temperature and places, that is, obtain the crystal formation D of 38.2mg De Luogewei sodium salts.
Embodiment 23
The crystal formation C of 45mg De Luogewei sodium salts prepared by embodiment 10 is put into 130 DEG C of baking ovens, in 130 DEG C of holdings To solvent is sloughed completely, take out room temperature and place within 40 minutes, that is, obtain the crystal formation D of 38.2mg De Luogewei sodium salts.
Sample prepared by embodiment 16~23 has XRPD same or analogous with the sample of embodiment 15 figures, IR figures, PLM Figure, DSC figures, TGA figures and adsorption isothermal curve figure (not shown).Illustrate that the sample of embodiment 16~23 is phase with the sample of embodiment 15 Same material.
Embodiment 24
The known De Luogewei sodium salts crystal formation I of the preparation of 60mg preparation examples 1 is weighed, 5.0ml trifluoroethanols are added, 40 DEG C surpass Sound makes molten clear (concentration of the solution is known De Luogewei sodium salts crystal formation I 1 times of solubility in trifluoroethanol), then from So volatilization crystallization 2 days, obtains the crystal formation E of 69.0mg De Luogewei sodium salts.
XRPD figures are shown in Figure 33.
PLM figures are shown in Figure 34, are shown as rod shaped particles.
DSC figures are shown in Figure 35.
TGA figures are shown in Figure 36, display：Weightless 15.12% before 150 DEG C, it is roughly equal to containing a molecule trifluoroethanol.
IR figures are shown in Figure 37.
Embodiment 25
The known De Luogewei sodium salts crystal formation I of the preparation of 48mg preparation examples 1 is weighed, 5.0ml trifluoroethanols are added：Ethanol (1:1) mixed solvent, 30 DEG C of ultrasounds make that molten clear (concentration of the solution is known De Luogewei sodium salt crystal formation I in the mixing 0.8 times of solubility in solvent), then volatilization crystallization 3 days naturally, obtains the crystal formation E of 55.2mg De Luogewei sodium salts.
Embodiment 26
The known De Luogewei sodium salts crystal formation I of the preparation of 54mg preparation examples 1 is weighed, 5.0ml trifluoroethanols are added：Acetic acid second Ester (2:1) mixed solvent, 50 DEG C of ultrasounds make that molten clear (concentration of the solution is that known De Luogewei sodium salt crystal formation I are mixed at this 0.9 times of solubility in bonding solvent), then volatilization crystallization 1 day naturally, obtains the crystal formation E of 62.1mg De Luogewei sodium salts.
Embodiment 27
The known De Luogewei sodium salts crystal formation I of the preparation of 30mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added:Acetonitrile (1.5:1) mixed solvent, 20 DEG C of ultrasounds make that molten clear (concentration of the solution is that known De Luogewei sodium salt crystal formation I are mixed at this 0.5 times of solubility in bonding solvent), then volatilization crystallization 5 days naturally, obtains the crystal formation E of 34.5mg De Luogewei sodium salts.
Embodiment 28
The known De Luogewei sodium salts crystal formation I of the preparation of 12mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added:N-butanol (4:1) mixed solvent, 60 DEG C of ultrasounds make that molten clear (concentration of the solution is known De Luogewei sodium salt crystal formation I in the mixing 0.6 times of solubility in solvent), then volatilization crystallization 4 days naturally, obtains the crystal formation E of 13.8mg De Luogewei sodium salts.
Embodiment 29
48mg De Luogewei sodium salts crystal formation D of the invention are weighed, 5.0mL trifluoroethanols are added:Methyl alcohol (1:1) mixing is molten Agent, 45 DEG C of ultrasounds make that molten clear (concentration of the solution is De Luogewei sodium salts crystal formation D of the invention solubility in the mixed solvent 0.7 times), then volatilization crystallization 4 days naturally, obtains the crystal formation E of 55.2mg De Luogewei sodium salts.
Embodiment 30
The known De Luogewei sodium salts crystal formation I of the preparation of 18mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added:Acetic acid is different Propyl ester (1.6:1) mixed solvent, 45 DEG C of ultrasounds make that molten clear (this concentration is that known De Luogewei sodium salt crystal formation I are mixed at this 0.3 times of solubility in bonding solvent), then volatilization crystallization 5 days naturally, obtains the crystal formation E of 20.7mg De Luogewei sodium salts.
Embodiment 31
The known De Luogewei sodium salts crystal formation I of the preparation of 60mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added, ultrasound is molten Clearly (concentration of the solution is known De Luogewei sodium salts crystal formation I 1 times of solubility in trifluoroethanol), then toward molten clear liquid Middle addition 50mL ethanol, is stirred at room temperature and separates out within 1 hour solid, and filtering, filter cake is washed with 3.0mL trifluoroethanols, 30 DEG C of dryings 10 Hour, obtain the crystal formation E of 66.3mg De Luogewei sodium salts.
Embodiment 32
Weigh 54mg De Luogewei sodium salts crystal formation A of the invention, add 5.0mL trifluoroethanols, ultrasound it is molten it is clear (solution Concentration is De Luogewei sodium salts crystal formation A of the invention 0.9 times of solubility in trifluoroethanol), then toward adding in molten clear liquid 60mL ethyl acetate, is stirred at room temperature and separates out within 2 hours solid, and filtering, filter cake is washed with 3.0mL trifluoroethanols, and 25 DEG C of dryings 18 are small When, obtain the crystal formation E of 58.4mg De Luogewei sodium salts.
Embodiment 33
The known De Luogewei sodium salts amorphous article of the preparation of 48mg preparation examples 2 is weighed, 5.0mL trifluoroethanols are added, surpassed Sound is molten clear (concentration of the solution is known De Luogewei sodium salts amorphous article 0.8 times of solubility in trifluoroethanol), so Afterwards toward addition 75mL acetonitriles in molten clear liquid, it is stirred at room temperature and separates out within 5 hours solid, filtering, filter cake is washed with 3.0mL trifluoroethanols, 20 DEG C of dryings 24 hours, obtain the crystal formation E of 51.4mg De Luogewei sodium salts.
Embodiment 34
The known De Luogewei sodium salts crystal formation I of the preparation of 30mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added, ultrasound is molten Clearly (concentration of the solution is known De Luogewei sodium salts crystal formation I 0.5 times of solubility in trifluoroethanol), then toward molten clear 25mL methyl alcohol is added in liquid, 50 DEG C of stirrings separate out solid for 12 hours, and filtering, filter cake is washed with 3.0mL trifluoroethanols, 15 DEG C of dryings 28 hours, obtain the crystal formation E of 31.8mg De Luogewei sodium salts.
Embodiment 35
The known De Luogewei sodium salts crystal formation I of the preparation of 12mg preparation examples 1 is weighed, 5.0mL trifluoroethanols are added, ultrasound is molten Clearly (concentration of the solution is known De Luogewei sodium salts crystal formation I 0.2 times of solubility in trifluoroethanol), then toward molten clear 100mL n-butanols are added in liquid, is stirred at room temperature and is separated out within 24 hours solid, filtering, filter cake is washed with 3.0mL trifluoroethanols, 10 DEG C Dry 30 hours, obtain the crystal formation E of 12.4mg De Luogewei sodium salts.
Embodiment 36
The De Luogewei sodium salts crystal formation D of the invention of the preparation of 16mg preparation examples 1 is weighed, 5.0mL trifluoroethanols, ultrasound is added Molten clear (concentration of the solution is De Luogewei sodium salts crystal formation D of the invention 0.4 times of solubility in trifluoroethanol), it is then past 40mL isopropyl acetates are added in molten clear liquid, 40 DEG C of stirrings separate out solid for 20 hours, and filtering, filter cake is washed with 3.0mL trifluoroethanols Wash, 5 DEG C of dryings 48 hours obtain the crystal formation E of 16.4mg De Luogewei sodium salts.
Embodiment 37
Weigh 48mg De Luogewei sodium salts crystal formation A of the invention, add 5.0mL trifluoroethanols, ultrasound it is molten it is clear (solution Concentration is De Luogewei sodium salts crystal formation A of the invention 0.8 times of solubility in trifluoroethanol), then toward adding in molten clear liquid 75mL toluene, is stirred at room temperature and separates out within 13 hours solid, filtering, and filter cake washs with 3.0mL trifluoroethanols, 5 DEG C of dryings 48 hours, obtains To the crystal formation E of 48.1mg De Luogewei sodium salts.
Embodiment 38
The known De Luogewei sodium salts amorphous article of the preparation of 54mg preparation examples 2 is weighed, 5.0mL trifluoroethanols are added, surpassed Sound is molten clear (concentration of the solution is known De Luogewei sodium salts amorphous article 0.9 times of solubility in trifluoroethanol), so Afterwards toward addition 65mL isopropyl ethers in molten clear liquid, 60 DEG C of stirrings separate out solid for 16 hours, and filtering, filter cake is washed with 3.0mL trifluoroethanols Wash, 5 DEG C of dryings 48 hours obtain the crystal formation E of 51.6mg De Luogewei sodium salts.
Sample prepared by embodiment 25~38 has XRPD same or analogous with the sample of embodiment 24 figures, IR figures, PLM Figure, DSC figures and TGA figure (not shown).Illustrate that the sample of embodiment 25~38 and the sample of embodiment 24 are identical materials.
Embodiment 39
Prepare the tablet containing De Luogewei sodium salts crystal formation A of the invention.
Tablet (the every free alkali of De Luogewei containing 50mg) formula is as follows：
De Luogewei sodium salts crystal formation A of the invention：52.6mg
Mannitol：187.0mg
PVP：15.0mg
Sodium carboxymethyl starch：12.4mg
Microcrystalline cellulose：30.0mg
Magnesium stearate：3.0mg
Amount to：300.0mg
The preparation process of tablet is as follows：
With the scale of 10,000, De Luogewei sodium salts crystal formation A of the invention is mixed with mannitol using equal increments method Close uniform, then after be well mixed with microcrystalline cellulose, sodium carboxymethyl starch, PVP, magnesium stearate, be placed in pressure in tablet press machine Piece, adjustment sheet weight, obtains final product respective tablets.
Embodiment 40-43
Prepare crystal formation B, crystal formation C, the tablet of crystal formation D and crystal formation E containing De Luogewei sodium salts of the present invention respectively.
Each tablet formulation is as follows：The crystal formation A of the Sino-German Roger's Wei sodium salt of embodiment 39 is replaced with into present invention preparation respectively The crystal formation B of De Luogewei sodium salts, crystal formation C, crystal formation D and crystal formation E, wherein, the crystal formation B, crystal formation C, crystal formation D and crystal formation E's matches somebody with somebody The mole dosage of Fang Zhongde Roger's Weis and De Luogewei sodium salt crystal formations A be formulated in it is identical, other components in each formula also with It is identical in embodiment 39.
The preparation process of each tablet is also with embodiment 39.
Embodiment 44
Tablet (plain piece) prepared by embodiment 39~43 is coated.
The formula of coating powder is following (consumption of every)：
Iron oxide yellow：3.0mg
Polyethylene glycol 8.0mg
Talcum powder 2.0mg
Titanium dioxide 2.0mg
Amount to：15.0mg
The operating procedure of coating：Tablet (plain piece) prepared by embodiment 39~43, is matched somebody with somebody by high-efficiency coating machine with above-mentioned The coating powder that Fang Zufen is mixed with is coated.
Test case 1
Crystal formation A, known De Luogewei sodium salts crystal formation I and known De Luogewei for De Luogewei sodium salts of the present invention Sodium salt monohydrate, carries out stability competitive assay and compares, and the results are shown in Table 1.
The operating process of the stability competitive assay is：The De Luogewei sodium salts of the present invention of equivalent (250mg) are taken respectively Crystal formation A, preparation example 1 prepare known De Luogewei sodium salts crystal formation I and preparation example 3 prepare known De Luogewei sodium salts Monohydrate, is placed in 3mL water after mixing, forms suspension, after stirring 7 days at room temperature, carries out XRPD signs.The results are shown in Table 1.
The stability competitive assay result of table 1
As seen from the results in Table 1：By at room temperature, in water magma stability competitive assay, it is known that De Luogewei sodium Salt crystal formation I and known De Luogewei sodium salts monohydrate are changed into De Luogewei sodium salts crystal formation A of the invention, and of the invention De Luogewei sodium salt crystal formations A keep crystal formation it is constant, illustrate De Luogewei sodium salts crystal formation A of the invention than known De Luogewei Sodium salt crystal formation I and known De Luogewei sodium salts monohydrate are more stable, so as to be more suitable for the wet granulation technology of solid pharmaceutical preparation, The stable crystal form in the wet-granulation process of Aquo System.
Test case 2
Crystal formation A, crystal formation B, crystal formation C, the crystal formation D and crystal formation E, control sample of the De Luogewei sodium salts of present invention preparation are taken respectively For known De Luogewei sodium salts crystal formation I, De Luogewei sodium salt amorphous article and De Luogewei sodium salts prepared by preparation example 1~3 Monohydrate, carries out the comparing of solubility, hygroscopicity, fusing point, decomposition temperature and granule-morphology in water at room temperature.The results are shown in Table 2.
Solubility is detected：50mg samples are taken in 20ml vials, 15ml deionized waters are added, 26 DEG C are stirred 1 day, sampling In filtering and being settled to 5ml volumetric flasks, with acetonitrile/water (1:1) constant volume, by HPLC detectable concentrations.
Decomposition temperature is detected：Detected by TGA and obtained.
Fusing point is detected：Detected by DSC and obtained.
Hygroscopicity is detected：Detect that the weight change in the range of 20%-80%RH is obtained by DVS.
Granule-morphology is detected：Detected by PLM and obtained.
The performance comparison result of the De Luogewei sodium salts of the different crystal forms of table 2
* note：De Luogewei sodium salt amorphous articles are stirred 5 minutes in water and are changed into De Luogewei sodium salt crystal formation I, therefore Both apparent solubilities are consistent.
Be can be seen that by the testing result of table 2：The crystal formation A, more known De Luogewei of De Luogewei sodium salts of the invention Sodium salt monohydrate, is less susceptible to moisture absorption；The crystal formation B of De Luogewei sodium salts of the invention is hydrated with known De Luogewei sodium salts one Thing compares, with solubility it is high, be difficult the advantages such as moisture absorption, granule-morphology be good；Crystal formation C, the crystalline substance of De Luogewei sodium salts of the invention Type D, crystal formation E and known De Luogewei sodium salts crystal formation I, De Luogewei sodium salt amorphous article and known De Luogewei sodium salts one Hydrate compares, with solubility advantage high；The crystal formation D of De Luogewei sodium salts of the invention, more known De Luogewei sodium Salt crystal formation I and De Luogewei sodium salt monohydrate, is less susceptible to moisture absorption.
Test case 3
Crystal formation A, the crystal formation B and crystal formation D of the De Luogewei sodium salts of present invention preparation are taken respectively, and control sample is made for preparation example 1 Standby known De Luogewei sodium salts crystal formation I, carries out the stability experiment of placement 10 days under hot and humid illumination condition.High temperature bar Part is 80 DEG C, and super-humid conditions are 90%RH, and illumination condition is 6000lx illumination.HPLC purity of the detection sample before and after placement and Maximum single miscellaneous content, the results are shown in Table 3.
The stability comparative result of the De Luogewei sodium salts of the different crystal forms of table 3
As shown in Table 3：Under conditions of hot and humid illumination 10 days, it is known that De Luogewei sodium salt crystal formation I purity reduction 2.8%, maximum single miscellaneous content increased 3.1%；And De Luogewei sodium salts crystal formation A purity of the invention reduces 0.5%, most Big single miscellaneous content increased 0.1%, and De Luogewei sodium salts crystal formation B purity of the invention reduces 0.3%, and maximum single miscellaneous content increases Add 0.05%, De Luogewei sodium salts crystal formation D purity of the invention reduces 0.4%, and maximum single miscellaneous content increase only 0.02%.
Therefore, De Luogewei sodium salts crystal formation A of the invention, the stability of crystal formation B and crystal formation D under hot and humid illumination are bright The aobvious De Luogewei sodium salt crystal formations I better than known to.
Cited all patent documents and non-patent publications in this specification, are incorporated by this by quoting with it Wen Zhong.
The above-mentioned general description of invention to being related in the present invention and the description to its specific embodiment should not be understood For be to the inventive technique scheme constitute limitation.Those skilled in the art's disclosure of the invention, can not disobey On the premise of the involved invention inscape of the back of the body, to above-mentioned general description or/and specific embodiment (including embodiment) In public technology feature increased, reduced or combined, formation belongs to other technical schemes of the invention.It is of the invention Protection domain should be determined by the scope of protection defined in the claims.

Claims (7)

1. the monohydrate crystal form B of structural formula De Luogewei sodium salts as follows,
Characterized in that, the crystal formation B has characteristic peak with the X-ray powder diffraction collection that 2 θ angles are represented in following position： 7.9 ± 0.2 °, 9.0 ± 0.2 °, 11.1 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 ° and 22.4 ± 0.2 °.
2. the monohydrate crystal form B of De Luogewei sodium salts according to claim 1, it is characterised in that the crystal formation B is with 2 θ The X-ray powder diffraction collection that angle is represented has characteristic peak in following position：7.9±0.2°、9.0±0.2°、11.1± 0.2°、13.8±0.2°、15.1±0.2°、15.9±0.2°、18.1±0.2°、22.4±0.2°、22.7±0.2°、23.4± 0.2 °, 26.0 ± 0.2 ° and 26.3 ± 0.2 °.
3. the monohydrate crystal form B of De Luogewei sodium salts according to claim 2, it is characterised in that the crystal formation B is with 2 θ The X-ray powder diffraction collection that angle is represented has characteristic peak and relative intensity in following position：
4. according to any one of claims 1 to 3 De Luogewei sodium salts monohydrate crystal form B, it is characterised in that it is described The FTIR spectrum of crystal formation B wave number be 2968,1645,1537,1502,1424,1320,1278,1258,1095, 1068th, 964,875,846,762 and 731cm-1Place has characteristic peak.
5. the preparation method of the De Luogewei sodium salt monohydrate crystal forms B any one of a kind of Claims 1 to 4, including Following steps：De Luogewei sodium salts are formed into suspension in the mixed solvent of water and organic solvent, wherein the organic solvent Selected from dimethyl sulfoxide, tetrahydrofuran, 1,4- dioxane, C3~C4Alcohol or its mixture, water are 1 with the volume ratio of organic solvent: 3~1:5, stirring and crystallizing, the crystal that will be separated out is separated, and is dried 10~48 hours at 10~30 DEG C, obtains the crystal formation B；
Preferably, the organic solvent is tetrahydrofuran or Isosorbide-5-Nitrae-dioxane；
Preferably, the water and the volume ratio of organic solvent are 1:4~1:5；
Preferably, the temperature of the crystallization is 10~60 DEG C, more preferably 30~50 DEG C；
Preferably, the time of the crystallization is 1~5 day, more preferably 1~3 day；
Preferably, the consumption of the Sino-German Roger's Wei sodium salt of the suspension is its solubility in the mixed solvent under recrystallization temperature 2~10 times, more preferably 2~5 times；
Preferably, the dry temperature is 10~20 DEG C；The dry time is 10~24 hours.
6. a kind of pharmaceutical composition, it includes treatment and/or the active constituents of medicine of prevention effective dose is selected from claims It is required that the monohydrate crystal form B of De Luogewei sodium salts any one of 1~4 or according to claim 5 preparation method The monohydrate crystal form B of the De Luogewei sodium salts for obtaining, and at least one pharmaceutically acceptable carrier or auxiliary agent.
7. the monohydrate crystal form B of the De Luogewei sodium salts any one of Claims 1 to 4 or according to claim 5 institute The monohydrate crystal form B for stating the De Luogewei sodium salts that preparation method is obtained is preparing the medicine for the treatment of and/or prevention HIV-1 infection In purposes.
CN201710242414.9A 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt Active CN106866702B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201410106767 2014-03-19
CN2014101067672 2014-03-19
CN201580000497.XA CN105121409B (en) 2014-03-19 2015-03-16 Crystalline form of dolutegravir sodium salt and preparation method therefor

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201580000497.XA Division CN105121409B (en) 2014-03-19 2015-03-16 Crystalline form of dolutegravir sodium salt and preparation method therefor

Publications (2)

Publication Number Publication Date
CN106866702A true CN106866702A (en) 2017-06-20
CN106866702B CN106866702B (en) 2019-03-19

Family

ID=54143757

Family Applications (5)

Application Number Title Priority Date Filing Date
CN201710242426.1A Active CN107056813B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201710242459.6A Active CN106831819B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201710242413.4A Active CN106866701B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201580000497.XA Active CN105121409B (en) 2014-03-19 2015-03-16 Crystalline form of dolutegravir sodium salt and preparation method therefor
CN201710242414.9A Active CN106866702B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt

Family Applications Before (4)

Application Number Title Priority Date Filing Date
CN201710242426.1A Active CN107056813B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201710242459.6A Active CN106831819B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201710242413.4A Active CN106866701B (en) 2014-03-19 2015-03-16 The crystal form and preparation method thereof of De Luogewei sodium salt
CN201580000497.XA Active CN105121409B (en) 2014-03-19 2015-03-16 Crystalline form of dolutegravir sodium salt and preparation method therefor

Country Status (2)

Country Link
CN (5) CN107056813B (en)
WO (1) WO2015139591A1 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016279A1 (en) * 2014-07-29 2016-02-04 Lek Pharmaceuticals D.D. Novel hydrates of dolutegravir sodium
EP3337479B1 (en) 2015-08-19 2023-12-13 Laurus Labs Limited Novel polymorphs of dolutegravir and salts thereof
WO2017046131A1 (en) * 2015-09-15 2017-03-23 Ratiopharm Gmbh Processes for preparing solid state forms of dolutegravir sodium
WO2017208105A1 (en) 2016-05-30 2017-12-07 Lupin Limited Novel crystalline form of dolutegravir sodium
EP3583107B1 (en) 2017-02-16 2020-11-18 Sandoz AG Crystalline form of cabotegravir sodium
US20210040116A1 (en) 2017-09-07 2021-02-11 Cipla Limited New Polymorphs of Dolutegravir Sodium
EP3993797A4 (en) * 2019-06-18 2023-10-25 Laurus Labs Limited Process and polymorphic forms of bictegravir and its pharmaceutically acceptable salts or co-crystals thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116764A1 (en) * 2005-04-28 2006-11-02 Smithkline Beecham Corporation Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
CN102245182A (en) * 2008-12-11 2011-11-16 盐野义制药株式会社 Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
CN102245572A (en) * 2008-12-11 2011-11-16 葛兰素史密丝克莱恩有限责任公司 Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
WO2013038407A1 (en) * 2011-09-14 2013-03-21 Mapi Pharma Ltd. Amorphous form of dolutegravir

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010011819A1 (en) * 2008-07-25 2010-01-28 Smithkline Beecham Corporation Chemical compounds
ES2870006T3 (en) * 2010-08-05 2021-10-26 Shionogi & Co Procedure for producing compounds having HIV integrase inhibitory activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116764A1 (en) * 2005-04-28 2006-11-02 Smithkline Beecham Corporation Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
CN102245182A (en) * 2008-12-11 2011-11-16 盐野义制药株式会社 Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
CN102245572A (en) * 2008-12-11 2011-11-16 葛兰素史密丝克莱恩有限责任公司 Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
WO2013038407A1 (en) * 2011-09-14 2013-03-21 Mapi Pharma Ltd. Amorphous form of dolutegravir

Also Published As

Publication number Publication date
CN106866701B (en) 2019-03-19
CN106831819B (en) 2019-01-04
CN106831819A (en) 2017-06-13
CN107056813B (en) 2019-07-30
CN107056813A (en) 2017-08-18
WO2015139591A1 (en) 2015-09-24
CN106866702B (en) 2019-03-19
CN105121409A (en) 2015-12-02
CN105121409B (en) 2017-05-24
CN106866701A (en) 2017-06-20

Similar Documents

Publication Publication Date Title
CN105121409B (en) Crystalline form of dolutegravir sodium salt and preparation method therefor
CN105121434B (en) Canagliflozin monohydrate and its crystal formation, their preparation method and purposes
CN105693624B (en) Macitentan crystal and preparation method thereof, its pharmaceutical composition and purposes
CN106279121B (en) The salt and crystal form or amorphous article, preparation method, pharmaceutical composition and purposes containing them of a kind of compound
WO2022121670A1 (en) Crystal form of tolebrutinib, preparation method therefor and use thereof
EP3176173B1 (en) Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
WO2017202351A1 (en) New crystal form of sodium-glucose co-transporter inhibitor medicine and preparation method and use thereof
CN111868057B (en) Solid form of dihydropyrimidine compound, preparation method and application thereof
CN106279126B (en) Afatinib acid-addition salts and its crystal form, preparation method and pharmaceutical composition
CN104918937A (en) Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof
CN108239055A (en) A kind of THR1442 L-Aspartic acids eutectic, preparation method and pharmaceutical composition
CN106928228B (en) Ao Gelieting salt and its crystal form, their preparation method and pharmaceutical composition
CN106146446A (en) The clean semihydrate of Da Gelie and crystal formation, its preparation method and pharmaceutical composition
CN105229001A (en) The antibiotic crystal formation of Yi Zhong oxazolidinone and preparation method, composition and purposes
CN105315266B (en) The crystal form of 1- { the fluoro- 4- of 2- [5- (4- isobutyl phenenyl) -1,2,4- oxadiazoles -3- base]-benzyl } -3- azetidinecarboxylic acid
CN108299412A (en) The addition salts and its crystal form and pharmaceutical composition of a kind of S1P1 receptor stimulating agents
AU2015276857B2 (en) Anhydrous crystalline free base form of-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzisoxazole
CN105367492B (en) His quinoline not crystal form of moral and preparation method thereof, its pharmaceutical composition and purposes
TW202227406A (en) Polymorphs of an ssao inhibitor
CN105308043B (en) Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes
CN110234639A (en) Crystal form for pyrrole method Buddhist nun and preparation method thereof and pharmaceutical composition
CN105949183B (en) Crystal form of Azilsartan and preparation method thereof
CN105085421B (en) Bit piperazine fumarate difficult to understand, hydrate, crystal formation and preparation method thereof
CN105732538B (en) Than Si Tapamo hydrochlorates and preparation method thereof, pharmaceutical composition and purposes
WO2018130226A1 (en) New crystal form of riociguat, preparation method and use thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190821

Address after: 310018 Room 2B05, Building 452, No. 6 Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province

Patentee after: Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd

Address before: 310018 room 2B12, building 452, No. 6, Hangzhou Economic & Technological Development Zone, Hangzhou, Zhejiang, China

Patentee before: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY CO., LTD.