CN106866701B - The crystal form and preparation method thereof of De Luogewei sodium salt - Google Patents

The crystal form and preparation method thereof of De Luogewei sodium salt Download PDF

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CN106866701B
CN106866701B CN201710242413.4A CN201710242413A CN106866701B CN 106866701 B CN106866701 B CN 106866701B CN 201710242413 A CN201710242413 A CN 201710242413A CN 106866701 B CN106866701 B CN 106866701B
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crystal form
sodium salt
luogewei sodium
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luogewei
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CN106866701A (en
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宋小叶
盛晓霞
盛晓红
贾强
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Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd
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HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • 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
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    • 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
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Abstract

The present invention relates to the novel crystal forms of De Luogewei sodium salt.Compared to the known crystal form of De Luogewei sodium salt, novel crystal forms of the invention have one or more beneficial properties, such as water stability is good, solubility is high, not easy to moisture absorption, excellent storage stability, granule-morphology are good.The invention further relates to the preparation method of the De Luogewei sodium salt novel crystal forms, its pharmaceutical composition and its it is used to prepare treatment and/or prevents the purposes in the drug that HIV-1 infects.

Description

The crystal form and preparation method thereof of De Luogewei sodium salt
The application be on October 10th, 2015 enter China application No. is 201580000497.X (PCT/CN2015/ 074293, international filing date on March 16th, 2015) patent application " crystal form and preparation method thereof of De Luogewei sodium salt " point Case application.
Technical field
The present invention relates to medicine crystal technical fields.Crystal form and its preparation side in particular to De Luogewei sodium salt Method.
Background technique
De Luogewei (English name dolutegravir) is that GlaxoSmithKline PLC drugmaker is public with Japanese Shionogi A kind of novel hiv integrase inhibitor that department researches and develops hand in hand, the inhibitor are intended to by inhibiting the diffusion of virus to treat Chinese mugwort Grow disease.It obtains U.S. FDA approval listing in August, 2013, and trade name TIVICAY, sodium salt containing De Luogewei is 50mg oral tablet Agent.The medicine is approved the extensive crowd for HIV infection, i.e., before never received HIV therapy and received anti-hiv therapy Infected patient, the HIV infection patient including having been used by the treatment of other integrase inhibitors before can apply.The medicine also goes through For the age 12 years old or more, at least 40 kilograms of weight, do not treated or by treatment but do not received other integrases suppression The children of preparation for treating, the recommended dose to above-mentioned child patient are 50mg, are taken orally one time a day.
The chemical name of De Luogewei sodium salt are as follows: (4R, 12aS) -9- { [(2,4 difluorobenzene base) methyl] carbamyl Base } -4- methyl -6,8- dioxo -3,4,6,8,12,12a- hexahydro -2H- pyrido [1 ', 2 ': 4,5] pyrazine is simultaneously [2,1-b] [1,3] oxazines -7- sodium alkoxide；English name are as follows: dolutegravir sodium or GSK1349572, chemical formula are as follows: C20H18F2N3NaO5；Molecular weight are as follows: 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 salt and its monohydrate, and uses solid-state13C-NMR, XRPD and IR are to moral sieve The crystal form of Ge Wei, De Luogewei sodium salt and De Luogewei sodium salt monohydrate is characterized.To be incited somebody to action in the present invention convenient for distinguishing The crystal form of De Luogewei sodium salt disclosed in WO2010/068253A1 is referred to as " crystal form I ".
Patent document WO2013/038407A1 discloses the amorphous article and preparation method thereof of De Luogewei sodium salt, is used in combination XRPD, DSC, TGA, FTIR, FT-Raman characterize it.
The present inventor is to De Luogewei sodium salt crystal form I, De Luogewei sodium salt monohydrate and moral Roger disclosed in document Wei sodium salt amorphous article has carried out repeating test and nature examination, as the result is shown: De Luogewei sodium salt crystal form I and De Luogewei sodium The stability of salt monohydrate is bad, cannot maintain original crystal habit, and they in stability competitive assay in water Dissolubility it is relatively low, with certain hygroscopicity, such property make its pharmaceutical preparation there are activity substance contents it is unstable, The problems such as impurity content increases in production poor reproducibility, storage process, drug effect declines.In addition, De Luogewei sodium salt amorphous article In water, it stirs at room temperature 5 minutes and is changed into crystal form 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 pharmaceutical ingredient form, expand original selected by formulation development Expect form, there is still a need for the novel crystal forms of exploitation De Luogewei sodium salt for this field.
Summary of the invention
In view of the deficiencies of the prior art, the purpose of the present invention is solve by providing the novel crystal forms of De Luogewei sodium salt Know crystal form there are the problem of.Meanwhile the invention further relates to the preparation method of the novel crystal forms and its pharmaceutical compositions and purposes.
The novel crystal forms are compared with known crystal form, and have at least one following favorable property: stability is good, such as crystal form Stability, thermal stability, chemical stability, mechanical stability, storage stability etc.；Dissolubility is good；Dissolution rate is fast；Crystallization Degree is high；It is not easy to moisture absorption；It is easy to purify and handle；Chemical purity is high；Low-residual solvent；Granule-morphology is good；Suitable preparation can add It is work such as good fluidity, advantageous powder viscosity, tightness and rammability, apparent good；Improve bioavilability, preparation medicine Effect；Extend preparation storage life；It is suitble to novel form application etc..
Purpose according to the present invention, the crystal form A that the present invention provides De Luogewei sodium salt (are referred to as " crystal form in the present invention A”)。
The crystal form A is the anhydride of De Luogewei sodium salt, and structural formula is as follows:
It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form A is indicated with 2 θ angles has 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 X-ray powder diffraction collection that the crystal form A is indicated with 2 θ angles has characteristic peak 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 X-ray powder diffraction collection that the crystal form A is indicated with 2 θ angles has feature in following position Peak and relative intensity:
。
Without limitation, a representative instance of the crystal form A has X-ray powder diffraction figure as shown in Figure 10.
The FTIR spectrum of the crystal form A wave number be 2942,1641,1537,1503,1424,1321,1278, 1258,1094,1069,964,854,763 and 722cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) map of the crystal form A is shown: sample weightlessness 1.0% before 150 DEG C is anhydride, point Solving temperature is 366 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal form A is shown: it is in 312 DEG C of beginning fusion and decompositions.
The preparation method of the crystal form A, comprising the following steps: by known De Luogewei sodium salt in water and organic solvent In the mixed solvent forms suspension, wherein the organic solvent is selected from acetonitrile, Isosorbide-5-Nitrae-dioxane, acetone, butanone or its mixing The volume ratio of object, water and organic solvent is 3:1~5:1, and crystal separation, the drying of precipitation are obtained the crystal form by stirring and crystallizing A。
Preferably, the organic solvent is acetonitrile or Isosorbide-5-Nitrae-dioxane.
Preferably, the volume ratio of the water and organic solvent is 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, the dosage of known De Luogewei sodium salt is that it is molten in the mixing under crystallization temperature in the suspension 2~10 times of solubility, more preferably 2~5 times in agent.
Preferably, the temperature of the drying is 10~60 DEG C, more preferably 10~40 DEG C.
Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.
The preparation method of above-mentioned crystal form A uses the crystallization mode of magma, is (to have the supersaturated solution of sample insoluble Solid presence) it stirs in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal form A, the known De Luogewei sodium salt, including published De Luogewei sodium salt Various crystal forms or amorphous article, for example including but be not limited to according to the description side patent document WO2010068253A1 embodiment 1l The De Luogewei sodium salt crystal form I of method preparation, or according to 3.1 method I of patent document WO2013038407A1 embodiment 1 preparation De Luogewei sodium salt amorphous article.
Crystal form A has beneficial property below:
1. the stability competitive assay comparison for passing through magma in water, it is known that De Luogewei sodium salt crystal form I and moral Roger Wei sodium salt monohydrate cannot maintain original crystal habit, be transformed into crystal form A, and crystal form A is protected under same experiment condition It is constant to hold crystal form.
2. crystal form A room temperature, 10%~90%RH of relative humidity drier in place 4 months, crystal form and fusing point are not Become.
After 3. crystal form A is stored 10 days under the high temperature and humidity illumination condition of 80 DEG C of -90%RH-6000lx, under purity Drop and largest single impurity content growth all be significantly lower than known De Luogewei sodium salt crystal form I data, illustrate its stability compared with Known De Luogewei sodium salt crystal form I is good.
4. crystal form A of the invention is in 20%-80% RH range compared with known Roger's Wei sodium salt monohydrate Interior weight change is 1.0% (known monohydrate weight change in 20%-80% RH range is 4.3%), is said Bright crystal form A of the invention is less easy to moisture absorption.
The above-mentioned property of crystal form A shows: with known De Luogewei sodium salt crystal form I and De Luogewei sodium salt monohydrate phase Than crystal form A stability of the invention is good.Crystal form A has better stability in water, is more suitable for the wet granulation of solid pharmaceutical preparation Oral administration mixed suspension is made in technique, has good preparation machinability in Aquo System；The excellent storage stability of crystal form A, It is suitable for the environmental condition of looser manufacture, storage and transport, preparation can preferably be fought due to temperature, humidity, crystalline substance The problems such as issuable active pharmaceutical ingredient contents of factors such as type variation are uneven, purity declines reduces thus bring and treats Imitate downside risk and security risk.
Purpose according to the present invention, the present invention provide the monohydrate crystal form B of De Luogewei sodium salt (in the present invention referred to as For " crystal form B ").
The crystal form B is the hydrate of De Luogewei sodium salt, and every mole of crystal form B contains about 1 mole of water, and structural formula is such as Shown in lower:
It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form B is indicated with 2 θ angles has 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 X-ray powder diffraction collection that the crystal form B is indicated with 2 θ angles 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 °.
It is highly preferred that the X-ray powder diffraction collection that the crystal form B is indicated with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of the crystal form B has X-ray powder diffraction figure as shown in figure 16.
The FTIR spectrum of the crystal form B wave number be 2968,1645,1537,1502,1424,1320,1278, 1258,1095,1068,964,875,846,762 and 731cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) map of the crystal form B is shown: sample is hydrate；Weightlessness 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 form B is shown: it is in 349 DEG C of beginning fusion and decompositions.
The preparation method of the crystal form B, comprising the following steps: De Luogewei sodium salt is molten in the mixing of water and organic solvent Suspension is formed in agent, wherein the organic solvent is selected from dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, C3~C4Alcohol or its The volume ratio of mixture, water and organic solvent is 1:3~1:5, and stirring and crystallizing separates the crystal of precipitation, at 10~30 DEG C It is 10~48 hours dry, obtain the crystal form B.
The C3~C4Alcohol can be or mixtures thereof normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol.
Preferably, the organic solvent is tetrahydrofuran or Isosorbide-5-Nitrae-dioxane.
Preferably, the volume ratio of the water and organic solvent is 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 dosage of the Sino-German Roger's Wei sodium salt of the suspension is that it is molten in the in the mixed solvent under crystallization temperature 2~10 times of Xie Du, more preferably 2~5 times.
Preferably, the temperature of the drying is 10~20 DEG C.
Preferably, the time of the drying is 10~24 hours.
The preparation method of above-mentioned crystal form B uses the crystallization mode of magma, is (to have the supersaturated solution of sample insoluble Solid presence) it stirs in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal form B: the De Luogewei sodium salt may include each of known De Luogewei sodium salt Kind of crystal form or amorphous article, for example including but be not limited to describe method system according to patent document WO2010068253A1 embodiment 1l Standby known De Luogewei sodium salt crystal form I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiment 1 Known De Luogewei sodium salt amorphous article；The De Luogewei sodium salt can also include De Luogewei sodium salt of the invention Crystal form A or crystal form D.
Crystal form B has beneficial property below:
1. solubility is 2.1mg/mL to crystal form B in water at room temperature, relatively known De Luogewei sodium salt monohydrate it is molten Xie Du (solubility is 1.7mg/mL in water at room temperature for it) is high.
After 2. crystal form B is stored 10 days under the high temperature and humidity illumination condition of 80 DEG C of -90%RH-6000lx, under purity The growth of drop and largest single impurity content is significantly lower than the data of known De Luogewei sodium salt crystal form I, has illustrated its stability more The De Luogewei sodium salt crystal form I known is good.
3. weight change of the crystal form B in 20%-80% RH range is only about 0.5%, relative to known moral It is Roger's Wei sodium salt monohydrate crystal form (its weight change in 20%-80% RH range is about 4.3%), known De Luogewei sodium salt crystal form I (its weight change in 20%-80% RH range is about 1.1%) is less easy to moisture absorption.
4. crystal form B is rod shaped particles, the particle than known De Luogewei sodium salt monohydrate is big.
The above-mentioned property of crystal form B shows: with known De Luogewei sodium salt crystal form I or known one water of De Luogewei sodium salt It closes object to compare, crystal form B of the present invention has the advantages that solubility height, excellent storage stability, not easy to moisture absorption, granule-morphology is good.It is made Agent can have higher dissolution rate and better bioavilability；Mobility of particle is good, convenient for the precise in preparation production With topple over, improve batch reproducibility；The stability of preparation is good, is suitable for the environmental condition of looser manufacture, storage and transport, Preferably confrontation due to the issuable active pharmaceutical ingredient content of the factors such as environment temperature, humidity, illumination is uneven, under purity The problems such as drop, reduces thus bring curative effect downside risk and security risk.
Purpose according to the present invention, the present invention provide the n-butanol solvent compound crystal form C of De Luogewei sodium salt (in the present invention In referred to as " crystal form C ").
The crystal form C is the n-butanol solvent compound of De Luogewei sodium salt, and every mole of crystal form C contains about 1 mole of positive fourth Alcohol, structural formula are as follows:
It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form C is indicated with 2 θ angles has 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 X-ray powder diffraction collection that the crystal form C is indicated with 2 θ angles has characteristic peak 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 X-ray powder diffraction collection that the crystal form C is indicated with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of the crystal form C has X-ray powder diffraction figure as shown in figure 22.
The FTIR spectrum of the crystal form C wave number be 3277,2956,2930,2873,1648,1624,1526, 1506,1428,1283,1251,1087,981,839 and 743cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) map of the crystal form C is shown: being had 15.17% weightlessness before 150 DEG C of sample, is roughly equal to and contains One molecule n-butanol, decomposition temperature are 367 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal form C is shown: it is in 338 DEG C of beginning fusion and decompositions.
The preparation method of the crystal form C, comprising the following steps: De Luogewei sodium salt is formed into suspension in n-butanol, Crystal separation, the drying of precipitation are obtained the crystal form C by stirring and crystallizing.
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 dosage of the Sino-German Roger's Wei sodium salt of the suspension is its solubility in n-butanol under crystallization temperature 2~10 times, more preferably 2~5 times.
Preferably, the temperature of the drying is 10~60 DEG C, more preferably 10~40 DEG C.
Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.
The preparation method of above-mentioned crystal form C uses the crystallization mode of magma, is (to have the supersaturated solution of sample insoluble Solid presence) it stirs in a solvent, obtain required crystal.
In the preparation method of above-mentioned crystal form C, the De Luogewei sodium salt may include each of known De Luogewei sodium salt Kind of crystal form or amorphous article, for example including but be not limited to describe method system according to patent document WO2010068253A1 embodiment 1l Standby known De Luogewei sodium salt crystal form I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiment 1 Known De Luogewei sodium salt amorphous article；The De Luogewei sodium salt can also include De Luogewei sodium salt of the invention Crystal form A or crystal form D.
Crystal form C has beneficial property below:
1. solubility is 4.6mg/mL to crystal form C in water at room temperature, the solubility of relatively known De Luogewei sodium salt crystal form I (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of relatively known De Luogewei sodium salt monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high.
2. crystal form C room temperature, 10%~90%RH of relative humidity drier in place 4 months, crystal form is constant.
The above-mentioned property of crystal form C shows: with known De Luogewei sodium salt crystal form I and known one water of De Luogewei sodium salt It closes object to compare, crystal form C of the invention has the advantages that solubility height, excellent storage stability.Preparation can have higher dissolution rate With better bioavilability, and adapt to the environmental condition of looser manufacture, storage and transport, preferably confrontation due to when Between, the problems such as issuable active pharmaceutical ingredient content of factors such as humidity is uneven, purity decline, reduce thus bring and treat Imitate downside risk and security risk.
Purpose according to the present invention, the crystal form D that the present invention provides De Luogewei sodium salt (are referred to as " crystal form in the present invention D”)。
The crystal form D is the anhydride of De Luogewei sodium salt, and structural formula is as follows:
It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form D is indicated with 2 θ angles has 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 X-ray powder diffraction collection that the crystal form D is indicated with 2 θ angles has characteristic peak 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 X-ray powder diffraction collection that the crystal form D is indicated with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of the crystal form D has X-ray powder diffraction figure as shown in figure 27.
The FTIR spectrum of the crystal form D wave number be 2922,1636,1621,1531,1504,1425,1317, 1280,1254,1198,1110,964,858 and 744cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) map of the crystal form D is shown: sample decomposition temperature is about 349 DEG C.
Differential scanning calorimetric (DSC) figure of the crystal form D is shown: it is in 345 DEG C of beginning fusion and decompositions.
The preparation method of the crystal form D, using any one in following preparation method:
(1) by the n-butanol solvent compound crystal form C of De Luogewei sodium salt with 5~20 DEG C/min of heating rate from room temperature 150 DEG C of desolventizing temperature are warming up to, 15~35 minutes are kept at 150 DEG C to solvent is sloughed completely, then with 5~20 DEG C/minute The cooling rate of clock is cooled to room temperature, and obtains the crystal form 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 cooling rate is 10~20 DEG C/min.
(2) the n-butanol solvent compound crystal form C of De Luogewei sodium salt is placed 25~40 in 130~150 DEG C of environment It minute to sloughing solvent completely, then is placed directly at room temperature, obtains the crystal form 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 form D uses the crystallization mode of high temperature desolventizing.
Crystal form D has beneficial property below:
1. solubility is 4.2mg/mL to crystal form D in water at room temperature, the solubility of relatively known De Luogewei sodium salt crystal form I (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of relatively known De Luogewei sodium salt monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high.
After 2. crystal form D is stored 10 days under the high temperature and humidity illumination condition of 80 DEG C of -90%RH-6000lx, under purity The growth of drop and largest single impurity content is significantly lower than the data of known De Luogewei sodium salt crystal form I, has illustrated its stability more The De Luogewei sodium salt crystal form I known is good.
3. crystal form D weight change in 20%-80% RH range is only about 0.1%, relative to known moral sieve Lattice Wei sodium salt crystal form I (its weight change in 20%-80% RH range is about 1.1%) and known De Luogewei sodium Salt monohydrate (its weight change in 20%-80% RH range is about 4.3%) is less easy to moisture absorption.
4. crystal form D room temperature, 10%~90%RH of relative humidity drier in place 4 months, crystal form is constant.
The above-mentioned property of crystal form D shows: with known De Luogewei sodium salt crystal form I and known one water of De Luogewei sodium salt It closes object to compare, crystal form D of the invention has the advantages that solubility is high, not easy to moisture absorption, excellent storage stability.The solid system of can satisfy The requirement of agent, machinability is good, and batch reproducibility is good, and preparation has higher dissolution rate and better bioavilability, And adapt to the environmental condition of looser manufacture, storage and transport, preferably confrontation due to the factors such as time, humidity there may be The problems such as active pharmaceutical ingredient content is uneven, purity decline, reduce thus bring curative effect downside risk and security risk.
Purpose according to the present invention, the present invention provide the trifluoroethanol solvate crystal form E of De Luogewei sodium salt (in this hair In bright referred to as " crystal form E ").
The crystal form E is the trifluoroethanol solvate of De Luogewei sodium salt, and every mole of crystal form E contains about 1 mole Trifluoroethanol, structural formula are as follows:
It is radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form E is indicated with 2 θ angles has 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 X-ray powder diffraction collection that the crystal form E is indicated with 2 θ angles has characteristic peak 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 X-ray powder diffraction collection that the crystal form E is indicated with 2 θ angles has feature in following position Peak and relative intensity:
Without limitation, a representative instance of the crystal form E has the X-ray powder diffraction figure as shown in 33.
The FTIR spectrum of the crystal form E wave number be 3419,3076,1641,1536,1503,1424,1321, 1282,1258,1069,1023,963,763 and 722cm-1Place has characteristic peak.
Thermogravimetric analysis (TGA) map of the crystal form E is shown: being had 15.1% weightlessness before 150 DEG C of sample, is 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 form E shows it in 337 DEG C of beginning fusion and decompositions.
The preparation method of the crystal form E, using any one in following preparation method:
(1) De Luogewei sodium salt is formed into solution in the in the mixed solvent of trifluoroethanol or trifluoroethanol and organic solvent, The organic solvent is selected from C1~C4Alcohol, C4~C5Or mixtures thereof ester, acetonitrile, then the crystallization that volatilizees naturally, obtain the crystal form E.
The C1~C4Alcohol can be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol；The C4~C5Ester It can be ethyl acetate or isopropyl acetate.
Preferably, the organic solvent is selected from ethyl alcohol, ethyl acetate or acetonitrile.
Preferably, the volume ratio of the trifluoroethanol and organic solvent is 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 solution is that De Luogewei sodium salt is molten in trifluoroethanol or the mixing 0.2~1 times of solubility, preferably 0.5~1 times, more preferably 0.8~1 times in agent.
The preparation method (1) of above-mentioned crystal form E uses the crystallization mode of nature volatilization crystallization.Concrete operations are: by sample Clear solution be placed in open glass bottle, open or cover punching, volatilization removal solvent naturally, acquisition crystal.
(2) anti-solvent is added into the trifluoroethanol solution of De Luogewei sodium salt, wherein the anti-solvent is selected from C1~C4 Alcohol, C4~C5Or mixtures thereof ester, isopropyl ether, acetonitrile, toluene, stirring and crystallizing obtain crystal separation, the drying of precipitation described Crystal form E.
The C1~C4Alcohol can be methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol or sec-butyl alcohol；The C4~C5Ester It can be ethyl acetate or isopropyl acetate.
Preferably, the anti-solvent is selected from ethyl alcohol, 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 solution is De Luogewei sodium salt under crystallization temperature in trifluoroethanol 0.2~1 times of solubility, more preferably 0.5~1 times.
Preferably, the temperature of the drying is 5~30 DEG C, more preferably 20~30 DEG C.
Preferably, the time of the drying is 10~48 hours, more preferably 10~24 hours.
The preparation method (2) of above-mentioned crystal form E use anti-solvent recrystallization crystallization mode, be sample is dissolved in it is good molten In agent, then appropriate anti-solvent is added, is precipitated crystal using dissolubility difference of the sample in different solvents.
In the preparation method of above-mentioned crystal form E, the De Luogewei sodium salt may include each of known De Luogewei sodium salt Kind of crystal form or amorphous article, for example including but be not limited to describe method system according to patent document WO2010068253A1 embodiment 1l Standby known De Luogewei sodium salt crystal form I is prepared according to 3.1 method I of patent document WO2013038407A1 embodiment 1 Known De Luogewei sodium salt it is unformedObject；The De Luogewei sodium salt can also include De Luogewei sodium salt of the invention Crystal form A or crystal form D.
Crystal form E has beneficial property below:
1. solubility is 3.7mg/mL to crystal form E in water at room temperature, the solubility of relatively known De Luogewei sodium salt crystal form I (solubility is 2.1mg/mL in water at room temperature for it) is high, also solubility (its of relatively known De Luogewei sodium salt monohydrate Solubility is 1.7mg/mL in water at room temperature) it is high, illustrate that crystal form E of the present invention has higher solubility.
2. crystal form E room temperature, 10%~90%RH of relative humidity drier in place 4 months, crystal form is constant.
The above-mentioned property of crystal form E shows: with known De Luogewei sodium salt crystal form I and known one water of De Luogewei sodium salt It closes object to compare, crystal form D of the invention has the advantages that solubility height, excellent storage stability.Preparation have higher dissolution rate and Better bioavilability, and adapt to the environmental condition of looser manufacture, storage and transport, preferably confrontation due to the time, The problems such as issuable active pharmaceutical ingredient content of the factors such as humidity is uneven, purity declines, reduces thus bring curative effect Downside risk and security risk.
The crystal form A of the above-mentioned Roger's Wei sodium salt of the present invention, crystal form B, crystal form C, crystal form D or crystal form E preparation method in:
" room temperature " refers to about 10~30 DEG C of temperature.
" stirring " can be completed, agitating mode such as magnetic agitation, mechanical stirring using the conventional method of this field 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, such as filtering or centrifugation.The filtering is usually It is filtered at room temperature with the pressure for being less than atmospheric pressure, preferably pressure is less than 0.09MPa.The concrete operations of the centrifugation Are as follows: it is intended to isolated sample and is placed in centrifuge tube, be centrifuged with 6000 revs/min of rate, until solid is all sink to centrifugation Bottom of the tube.The crystal obtained through " separation " can be washed further, wash solvent used preferably with crystal preparation method Used in solvent it is identical, the dosage of cleaning solvent is generally 0.3~1 times of solvent volume used in crystal preparation method.
" anhydride " refers to sample through TGA detection containing not more than 1.5% (weight ratio) or not more than 1.0% (weight Measure ratio) water.
The present invention is solved by providing crystal form A, crystal form B, crystal form C, crystal form D and the crystal form E of novel De Luogewei sodium salt Prior art crystal form there are the problem of, the novel crystal forms have at least one or more of beneficial property compared with known crystal form Matter, such as: higher solubility, dissolution rate, be not susceptible to polymorphic inversion and/or dehydration, calorifics and good mechanical stability, Agent of low hygroscopicity, better mobility, compressibility and good, the low-residual solvent of apparent density, storage stability etc..
In the present invention, " crystal " or " crystal form " refers to what the characterization of the X-ray diffractogram by shown in was confirmed.This field skill Art personnel are it is understood that experimental error therein depends on condition, the preparation of sample and the purity of sample of instrument.In particular, 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 may also change with the variation of experiment condition, so the sequence of peak intensity cannot be made For unique or deciding factor.In addition, the experimental error of peak angle degree is usually 5% or less, the error of these angles also should It is considered into, allows generally for ± 0.2 error.In addition, will cause peak angle due to the influence of the empirical factors such as height of specimen The overall offset of degree allows generally for certain offset.Thus, it will be appreciated by persons skilled in the art that any have and this The same or similar crystal form of the characteristic peak of invention map belongs within scope of the invention.
" crystal " or " crystal form " of the present invention be it is pure, single, do not mix any other crystal form substantially.The present invention In, " not having substantially " refers to that this crystal form contains other crystal forms less than 20% (weight) when being used to refer to novel crystal forms, especially few In other crystal forms of 10% (weight), more refer to other crystal forms less than 5% (weight), more refers to other crystalline substances less than 1% (weight) Type.
In addition, described pharmaceutical composition includes treatment and/or prevention effective dose the present invention also provides a kind of pharmaceutical composition Active pharmaceutical ingredient be selected from the crystal form A of De Luogewei sodium salt of the invention, crystal form B, crystal form C, crystal form D, crystal form E or according to Crystal form A, crystal form B, crystal form C, crystal form D, the crystal form E for the De Luogewei sodium salt of the invention that preparation method of the present invention obtains, and At least one pharmaceutically acceptable carrier or auxiliary agent.Described pharmaceutical composition can also include the other of De Luogewei sodium salt can The crystal form or its amorphous article of other officinal salts of medicinal crystal form or amorphous article or De Luogewei.Optionally, the medicine Compositions include one or more other active pharmaceutical ingredients, including but not limited to others antiviral drugs, such as are had There are the inverase such as reverse transcriptase inhibitor and/or protease inhibitors of different role mechanism.
Pharmaceutical preparation form appropriate can be made in described pharmaceutical composition, can be administered orally or parenterally.It is suitable for The pharmaceutical preparation of oral administration, solid oral dosage form is for example including tablet, granule, powder, pill, powder, capsule etc., liquid Body peroral dosage form is for example including solution, syrup, suspension, emulsion agent etc., De Luogewei of the invention in the suspension The crystal form of sodium salt remains solid form.Suitable for the pharmaceutical preparation of parenteral administration, for example including intravenous drip preparations, muscle or Subcutaneous injection agent, the suppository of per rectum administration, spray, the paste of intravaginal administration, the sucking preparation of intranasal administration or part The transdermal patch form of administration.Formula may be adapted to the quick release, sustained release or adjusting release of active constituent.
In solid oral dosage form, acceptable carrier or auxiliary agent include but is not limited in described pharmaceutical composition Chinese pharmacology: Diluent, for example, it is starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, calcium phosphate dibasic anhydrous, tricalcium phosphate, sweet Reveal alcohol, sorbierite, sugar etc.；Adhesive, for example, Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, polyethylene glycol, copolyvidone etc.；Disintegrating agent, such as starch, sodium carboxymethyl starch, hydroxyacetic acid form sediment Powder sodium, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide etc.；Lubricant, for example, it is stearic Acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate etc.；Glidant, such as colloidal silicon dioxide etc.；Compound is formed Agent, such as the 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 includes but is not limited to film forming agent, plasticizer, colorant, flavoring agent, 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 sterile water, normal saline solution, glucose solution, mannitol solution, vegetable oil, cod-liver oil, ethyl alcohol, third Alcohol, glycerol etc..Further, it is also possible to use the carriers such as polyethylene glycol, polypropylene glycol.Be suitble to parenteral in the case where, 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, it can be compatible with the other compositions in formula and harmless for sufferer.
Described pharmaceutical composition can be used that well known to a person skilled in the art methods to prepare.Prepare pharmaceutical composition When, the crystal form A of De Luogewei sodium salt of the present invention, crystal form B, crystal form C, crystal form D or crystal form E can pharmaceutically be connect with one or more The carrier or auxiliary agent received mix, and optionally, mix with one or more other active pharmaceutical ingredients.Solid pharmaceutical preparation can be with It is prepared by the techniques such as mixing, pelletizing.Liquid preparation can be prepared by techniques such as dissolution, dispersion, emulsifications.
Crystal form A, crystal form B, crystal form C, crystal form D or the crystal form E of De Luogewei sodium salt of the present invention have the integrase of virus Significant inhibiting effect, the integrase as retrovirus (including HIV-1, HIV-2, HTLV-1, SIV-1, FIV-1) inhibit Agent is especially used to prepare the drug for the treatment of and/or pre- preventing HIV infection.
In addition, the present invention provides a kind of method treated and/or prevention HIV-1 infects, the method includes giving needs Patient's treatment and/or the crystal form A selected from De Luogewei sodium salt of the invention of prevention effective dose, crystal form B, crystal form C, crystal form D, The foregoing pharmaceutical combination of crystal form E or crystal form A, crystal form B, crystal form C, crystal form D or crystal form E containing De Luogewei sodium salt of the present invention Object.Different dosage is used according to the difference of medication, patient age, weight and the state of an illness.Usually in the feelings of oral administration Under condition, each adult gives about 0.1mg~1000mg daily；In the case where parenteral, each adult gives about daily 0.05mg~500mg.
Detailed description of the invention
The XRPD figure that Fig. 1 is known De Luogewei sodium salt crystal form I prepared by preparation example 1.
The PLM figure that Fig. 2 is known Roger's Wei sodium salt crystal form I prepared by preparation example 1.
Fig. 3 is the adsorption isothermal curve figure of known De Luogewei sodium salt crystal form I prepared by preparation example 1.
The IR figure that Fig. 4 is known De Luogewei sodium salt crystal form I prepared by preparation example 1.
Fig. 5 is the XRPD figure of known De Luogewei sodium salt amorphous article prepared by preparation example 2.
Fig. 6 is the XRPD figure of known De Luogewei sodium salt monohydrate prepared by preparation example 3.
Fig. 7 is the PLM figure of known De Luogewei sodium salt monohydrate prepared by preparation example 3.
Fig. 8 is the adsorption isothermal curve figure of known De Luogewei sodium salt monohydrate prepared by preparation example 3.
Fig. 9 is the IR figure of known De Luogewei sodium salt monohydrate prepared by preparation example 3.
The XRPD figure that Figure 10 is the crystal form A of De Luogewei sodium salt of the present invention.
The PLM figure that Figure 11 is the crystal form A of De Luogewei sodium salt of the present invention.
The DSC figure that Figure 12 is the crystal form A of De Luogewei sodium salt of the present invention.
The TGA figure that Figure 13 is the crystal form A of De Luogewei sodium salt of the present invention.
Figure 14 is the adsorption isothermal curve figure of the crystal form A of De Luogewei sodium salt of the present invention.
The IR figure that Figure 15 is the crystal form A of De Luogewei sodium salt of the present invention.
The XRPD figure that Figure 16 is the crystal form B of De Luogewei sodium salt of the present invention.
The PLM figure that Figure 17 is the crystal form B of De Luogewei sodium salt of the present invention.
The DSC figure that Figure 18 is the crystal form B of De Luogewei sodium salt of the present invention.
The TGA figure that Figure 19 is the crystal form B of De Luogewei sodium salt of the present invention.
Figure 20 is the adsorption isothermal curve figure of the crystal form B of De Luogewei sodium salt of the present invention.
The IR figure that Figure 21 is the crystal form B of De Luogewei sodium salt of the present invention.
The XRPD figure that Figure 22 is the crystal form C of De Luogewei sodium salt of the present invention.
The PLM figure that Figure 23 is the crystal form C of De Luogewei sodium salt of the present invention.
The DSC figure that Figure 24 is the crystal form C of De Luogewei sodium salt of the present invention.
The TGA figure that Figure 25 is the crystal form C of De Luogewei sodium salt of the present invention.
The IR figure that Figure 26 is the crystal form C of De Luogewei sodium salt of the present invention.
The XRPD figure that Figure 27 is the crystal form D of De Luogewei sodium salt of the present invention.
The PLM figure that Figure 28 is the crystal form D of De Luogewei sodium salt of the present invention.
The DSC figure that Figure 29 is the crystal form D of De Luogewei sodium salt of the present invention.
The TGA figure that Figure 30 is the crystal form D of De Luogewei sodium salt of the present invention.
Figure 31 is the adsorption isothermal curve figure of the crystal form D of De Luogewei sodium salt of the present invention.
The IR figure that Figure 32 is the crystal form D of De Luogewei sodium salt of the present invention.
The XRPD figure that Figure 33 is the crystal form E of De Luogewei sodium salt of the present invention.
The PLM figure that Figure 34 is the crystal form E of De Luogewei sodium salt of the present invention.
The DSC figure that Figure 35 is the crystal form E of De Luogewei sodium salt of the present invention.
The TGA figure that Figure 36 is the crystal form E of De Luogewei sodium salt of the present invention.
The IR figure that Figure 37 is the crystal form E of De Luogewei sodium salt of the present invention.
Specific embodiment
The present invention makes and uses with further reference to following embodiment, the embodiment detailed description of the present invention crystal form 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 where bright range.
Acquire instrument and method used in data:
X-ray powder diffraction (XPRD): used instrument is Bruker D8 Advance diffractometer, Use copper target wavelength for the Ka X-ray of 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ angular instrument, Mo monochromator, Lynxeye detector.Instrument is calibrated using the preceding standard items (generally corundum) carried with instrument.Sample is at room temperature Test, the sample that needs are detected are placed on areflexia plate.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 microscope (the limited public affairs of the rectangular optical instrument in Shanghai Department).It takes a small amount of powder sample to be placed on glass slide, a small amount of mineral oil is added dropwise to better disperse powder sample, covered, Then sample is placed on the objective table of XP-500E polarization microscope, selects the shape of suitable amplification factor observing samples Looks are simultaneously taken pictures.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200 MDSC, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample of 1~10mg is taken to be placed in aluminium dish, usually with 10 DEG C/min heating rate sample is risen to 375 DEG C or 400 DEG C from 0 DEG C under the protection of 40mL/ minutes drying nitrogens.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.It usually takes the sample of 5~15mg to be placed in platinum crucible, adopts With segmentation high resolution detection mode, with 10 DEG C/min of heating rate by sample under the protection of 40mL/ minutes drying nitrogens 400 DEG C or 450 DEG C are risen to from room temperature.
Adsorption isothermal curve: data are picked up from TA Instruments Q5000 TGA, and instrument control software is Thermal Advantage, analysis software is Universal Analysis.The sample of 1~10mg is usually taken to be placed in platinum crucible, TA Software records sample is in relative humidity to the weight change in 0% change procedure from 0% to 80%.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 Data Analysis Software All it is OPUS, ATR equipment is generallyd use, in 600-4000cm-1Acquisition infrared absorption spectrum in range, sample and blank background Sweep time is 16 seconds, instrumental resolution 4cm-1。
High-efficient liquid phase analysis (HPLC) data are picked up from Agilent 1260, and instrument control software is Agilent chemistry work Stand B.04 version online, and analysis software is Agilent chem workstation B.04 version offline.Using C18 chromatographic column, 250mm*4.6mm, 35 DEG C of column temperature, wavelength 254nm, flow velocity 0.7mL/ minutes, sample volume 20 μ L, runing 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 in embodiment are commercially available unless otherwise instructed.
Temperature in embodiment is room temperature unless otherwise instructed.
In embodiment, the ratio of in the mixed solvent component is volume ratio unless otherwise instructed.
Ultrasound procedure in embodiment can promote sample to dissolve, and equipment is ultrasonic cleaner, carry out under 40kHz power 5 minutes.
Preparation example 1Prepare known De Luogewei sodium salt crystal form I
The side that known De Luogewei sodium salt crystal form I can be described according to patent document WO2010/068253A1 embodiment 1l Method is prepared.
It, will at 80 DEG C specifically the preparation method comprises the following steps: 12.0g De Luogewei is dissolved in 36mL ethyl alcohol by heating The NaOH aqueous solution of 14.5mL 2N is added in the solution, which is gradually cooling to room temperature, and filtering is washed with 50mL ethyl alcohol Simultaneously 50 DEG C of dryings are washed, De Luogewei sodium salt is obtained.
XRPD figure is shown in Fig. 1, the crystal form I mono- of display and De Luogewei sodium salt disclosed in patent document WO2010/068253A1 It causes.
PLM figure is shown in Fig. 2, is 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 range.
IR figure is shown in Fig. 4, shows consistent with the crystal form I of De Luogewei sodium salt disclosed in patent document WO2010/068253A1.
Preparation example 2Prepare known De Luogewei sodium salt amorphous article
Known De Luogewei sodium salt amorphous article can refer to 3.1 sides of patent document WO2013/038407A1 embodiment 1 Method I is prepared.
Specifically: the De Luogewei sodium salt crystal form I for weighing the preparation of 40mg preparation example 1, with ball mill with 200 revs/min Speed ball milling 200 minutes is to get arriving De Luogewei sodium salt amorphous article.
XRPD figure is shown in Fig. 5, and display is amorphous article without characteristic peak.
Preparation example 3Prepare known De Luogewei sodium salt monohydrate
What known De Luogewei sodium salt monohydrate can be described according to patent document WO2010/068253A1 embodiment 1m Method is prepared.
Specifically the preparation method comprises the following steps: 10g De Luogewei sodium salt is dissolved in 200mL tetrahydrofuran-water (4:1) solution at 30 DEG C In, add the 2N NaOH aqueous solution of 12mL.Mixture is stirred at room temperature 2 hours, is filtered, filter cake 100mL tetrahydro furan It mutters-water (4:1) solution and the washing of 100mL tetrahydrofuran, 85 DEG C of dryings obtain De Luogewei sodium salt monohydrate.
XRPD figure is shown in Fig. 6, the monohydrate of display and De Luogewei sodium salt disclosed in patent document WO2010/068253A1 Crystal form is consistent.
PLM figure is shown in Fig. 7, is shown as little particle.
Adsorption isothermal curve figure is shown in Fig. 8, display: weight change is 4.3% in 20%-80% RH range.
IR figure is shown in that Fig. 9, display and the monohydrate of De Luogewei sodium salt disclosed in patent document WO2010/068253A1 are brilliant Type is consistent.
Embodiment 1
The known De Luogewei sodium salt crystal form I of the preparation of 40mg preparation example 1 is weighed, adds 5.0mL water: acetonitrile (4:1) Mixed solvent formed suspension (in the suspension dosage of known De Luogewei sodium salt crystal form I under crystallization temperature its in institute 2 times for stating in the mixed solvent solubility), 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 dried in vacuo 10 hours, obtain 38.4mg De Luogewei sodium salt crystal form A.
XRPD figure is shown in Figure 10.
PLM figure is shown in Figure 11, display: for smaller, irregular particle.
DSC figure is shown in Figure 12.
TGA figure is shown in Figure 13, display: the weightlessness 1.0% before 150 DEG C is anhydride.
Adsorption isothermal curve figure is shown in Figure 14, display: weight change is 1.0% in 20%-80% RH range.
IR figure is shown in Figure 15.
Embodiment 2
The known De Luogewei sodium salt crystal form I of the preparation of 100mg preparation example 1 is weighed, 5.0mL water: Isosorbide-5-Nitrae-dioxy six is added The mixed solvent of ring (5:1) forms suspension, and (dosage of known De Luogewei sodium salt crystal form I is crystallization temperature in the suspension Its 5 times in the in the mixed solvent solubility down), this suspension is stirred 6 days at 50 DEG C, filtering, filter cake 1.5mL water: The mixed solvent of Isosorbide-5-Nitrae-dioxane (5:1) washs, 30 DEG C drying 15 hours, obtain 92.1mg De Luogewei sodium salt crystal form A.
Embodiment 3
The known De Luogewei sodium salt amorphous article of the preparation of 90mg preparation example 2 is weighed, addition 5.0mL water: acetone (4.5: 1) mixed solvent forms suspension, and (dosage of known De Luogewei sodium salt amorphous article is under crystallization temperature in the suspension Its 4.5 times in the in the mixed solvent solubility), this suspension is stirred 8 days at 40 DEG C, filtering, with 3.5mL water: acetone The mixed solvent of (4.5:1) washs, 10 DEG C drying 24 hours, obtain 80.9mg De Luogewei sodium salt crystal form A.
Embodiment 4
The known De Luogewei sodium salt amorphous article of the preparation of 100mg preparation example 2 is weighed, addition 5.0mL water: butanone (3: 1) mixed solvent forms suspension, and (dosage of known De Luogewei sodium salt amorphous article is under crystallization temperature in the suspension Its 10 times in the in the mixed solvent solubility), this suspension is stirred 14 days at 10 DEG C, filtering, filter cake 5.0mL water: The mixed solvent of butanone (3:1) washs, 60 DEG C drying 48 hours, obtain 17.4mg De Luogewei sodium salt crystal form A.
Sample prepared by embodiment 2~4 have with the same or similar XRPD of 1 sample of embodiment figure, IR figure, PLM figure, DSC figure, TGA figure and adsorption isothermal curve figure (not shown).Illustrate that 2~4 sample of embodiment and 1 sample of embodiment are identical objects Matter.
Embodiment 5
The known De Luogewei sodium salt crystal form I of the preparation of 60mg preparation example 1 is weighed, addition 5.0mL water: tetrahydrofuran (1: 4) mixed solvent formed suspension (in the suspension dosage of known De Luogewei sodium salt crystal form I be under crystallization temperature its At 2 times of the in the mixed solvent solubility), this suspension is stirred 1 day at 60 DEG C, filtering, filter cake 2.0mL water: tetrahydro The mixed solvent of furans (1:4) washs, and 10 DEG C are dried in vacuo 24 hours, obtains the crystal form B of 58.7mg De Luogewei sodium salt.
XRPD figure is shown in Figure 16.
PLM figure is shown in Figure 17, display: for rod shaped particles.
DSC figure is shown in Figure 18.
TGA figure is shown in Figure 19, display: weightless 6.2% (water containing surface 2.0%) before 150 DEG C is roughly equal to containing a molecular water.
Adsorption isothermal curve figure is shown in Figure 20, display: weight change is 0.5% in 20%-80% RH range, explanation It is not easy to moisture absorption.
IR figure is shown in Figure 21.
Embodiment 6
The crystal form A of 150mg De Luogewei sodium salt of the invention is weighed, adds 5.0mL water: Isosorbide-5-Nitrae-dioxane (1:5) Mixed solvent formed suspension (in the suspension dosage of De Luogewei sodium salt crystal form A of the invention be crystallization temperature under its 3 times of the in the mixed solvent solubility), this suspension is stirred 2 days at 50 DEG C, filtering, filter cake 4.0mL water: Isosorbide-5-Nitrae-two The mixed solvent of six ring of oxygen (1:5) washs, 15 DEG C drying 18 hours, obtain the crystal form B of 150.0mg De Luogewei sodium salt.
Embodiment 7
The crystal form D of 90mg De Luogewei sodium salt of the invention is weighed, add 5.0mL water: the mixing of normal propyl alcohol (1:4.5) is molten Dosage form at suspension (in the suspension dosage of De Luogewei sodium salt crystal form D of the invention be under crystallization 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 drying 14 hours, obtain the crystal form B of 86.0mg De Luogewei sodium salt.
Embodiment 8
The known De Luogewei sodium salt crystal form I of the preparation of 30mg preparation example 1 is weighed, addition 5.0mL water: dimethyl sulfoxide (1: 3) mixed solvent formed suspension (in the suspension dosage of known De Luogewei sodium salt crystal form I be under crystallization temperature its At 5 times of the in the mixed solvent solubility), this suspension is stirred 4 days at 20 DEG C, filtering, filter cake 3.0mL water: diformazan The mixed solvent of sulfoxide (1:3) washs, 18 DEG C drying 12 hours, obtain the crystal form B of 28.0mg De Luogewei sodium salt.
Embodiment 9
The known De Luogewei sodium salt amorphous article of the preparation of 300mg preparation example 2 is weighed, 5.0mL water: n-butanol is added The mixed solvent of (1:4.2) forms suspension, and (dosage of known De Luogewei sodium salt amorphous article is crystallization in the suspension At a temperature of its at 10 times of the in the mixed solvent solubility), 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 drying 10 hours, obtain 270.8mg De Luogewei sodium salt Crystal form B.
Sample prepared by embodiment 6~9 have with the same or similar XRPD of 5 sample of embodiment figure, IR figure, PLM figure, DSC figure, TGA figure and adsorption isothermal curve figure (not shown).Illustrate that 6~9 sample of embodiment and 5 sample of embodiment are identical objects Matter.
Embodiment 10
The known De Luogewei sodium salt crystal form I of the preparation of 50mg preparation example 1 is weighed, addition 5.0mL n-butanol, which is formed, to be suspended Liquid (in the suspension dosage of known De Luogewei sodium salt crystal form I be under crystallization 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-butanol, and 40 DEG C are dried in vacuo 10 hours, is obtained The crystal form C of 54.7mg De Luogewei sodium salt.
XRPD figure is shown in Figure 22.
PLM figure is shown in Figure 23, is shown as little particle.
DSC figure is shown in Figure 24.
TGA figure is shown in Figure 25, display: the weightlessness 15.2% before 150 DEG C is roughly equal to containing a molecule n-butanol.
IR figure is shown in Figure 26.
Embodiment 11
The known De Luogewei sodium salt crystal form I of the preparation of 75mg preparation example 1 is weighed, addition 5.0mL n-butanol, which is formed, to be suspended Liquid (in the suspension dosage of known De Luogewei sodium salt crystal form I be crystallization temperature under its in n-butanol solubility 3 Times), this suspension is stirred 18 hours at 40 DEG C, filtering, filter cake washs with 3.0mL n-butanol, 35 DEG C drying 13 hours, obtain The crystal form C of 80.3mg De Luogewei sodium salt.
Embodiment 12
The crystal form A of 125mg De Luogewei sodium salt of the invention is weighed, addition 5.0mL n-butanol forms suspension (suspension In liquid the dosage of the crystal form A of De Luogewei sodium salt of the invention be under crystallization temperature its 5 times of solubility in n-butanol), 30 DEG C stirring 24 hours, filtering, filter cake washed with 3.0mL n-butanol, 10 DEG C drying 48 hours, obtain 129.5mg De Luogewei sodium The crystal form C of salt.
Embodiment 13
The crystal form D of 25mg De Luogewei sodium salt of the invention is weighed, addition 5.0mL n-butanol forms suspension (suspension In liquid the dosage of De Luogewei sodium salt crystal form D of the invention be under crystallization temperature its 2 times of solubility in n-butanol), by this Suspension stirs 13 hours at 60 DEG C, and filtering, filter cake washs with 3.0mL n-butanol, 18 DEG C drying 16 hours, obtain 25.3mg moral The crystal form C of Roger's Wei sodium salt.
Embodiment 14
The known De Luogewei sodium salt amorphous article of the preparation of 250mg preparation example 2 is weighed, 5.0mL n-butanol solvent is added Forming suspension, (dosage of known De Luogewei sodium salt amorphous article is that it is molten in n-butanol under crystallization temperature in the 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-butanol, 60 DEG C of dryings 28 Hour, obtain the crystal form C of 244.7mg De Luogewei sodium salt.
Sample prepared by embodiment 11~14 has and the same or similar XRPD figure of 10 sample of embodiment, IR figure, PLM Figure, DSC figure and TGA figure (not shown).Illustrate that 11~14 sample of embodiment and 10 sample of embodiment are identical substances.
Embodiment 15
The crystal form C of 20mg De Luogewei sodium salt 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, are then cooled to room temperature with 10 DEG C/min to get 16.9mg moral sieve is arrived The crystal form D of lattice Wei sodium salt.
XRPD figure is shown in Figure 27.
PLM figure is shown in Figure 28, display: for little particle.
DSC figure is shown in Figure 29.
TGA figure is 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 figure is shown in Figure 32.
Embodiment 16
The crystal form C of 30mg De Luogewei sodium salt prepared by embodiment 10 is warming up to 150 DEG C with 8 DEG C/min, at 150 DEG C It is kept for 25 minutes to solvent is sloughed completely, is then cooled to room temperature with 15 DEG C/min to get 25.4mg De Luogewei sodium salt is arrived Crystal form D.
Embodiment 17
The crystal form C of 50mg De Luogewei sodium salt prepared by embodiment 10 is warming up to 150 DEG C with 5 DEG C/min, at 150 DEG C It is kept for 20 minutes to solvent is sloughed completely, is then cooled to room temperature with 20 DEG C/min to get 42.4mg De Luogewei sodium salt is arrived Crystal form D.
Embodiment 18
The crystal form C of 28mg De Luogewei sodium salt prepared by embodiment 10 is warming up to 150 DEG C with 15 DEG C/min, at 150 DEG C It is kept for 33 minutes to solvent is sloughed completely, is then cooled to room temperature with 8 DEG C/min to get 23.8mg De Luogewei sodium salt is arrived Crystal form D.
Embodiment 19
The crystal form C of 26mg De Luogewei sodium salt prepared by embodiment 10 is warming up to 150 DEG C with 20 DEG C/min, at 150 DEG C It is kept for 35 minutes to solvent is sloughed completely, is then cooled to room temperature with 5 DEG C/min to get 22.1mg De Luogewei sodium salt is arrived Crystal form D.
Embodiment 20
The crystal form C of 30mg De Luogewei sodium salt prepared by embodiment 10 is put into 140 DEG C of baking ovens, keep 35 minutes to complete Solvent is sloughed entirely, is taken out and is placed at room temperature for get the crystal form D of 25.4mg De Luogewei sodium salt is arrived.
Embodiment 21
The crystal form C of 50mg De Luogewei sodium salt prepared by embodiment 10 is put into 150 DEG C of baking ovens, keeps 25 at 150 DEG C Minute to solvent is sloughed completely, takes out and is placed at room temperature for get the crystal form D of 42.4mg De Luogewei sodium salt is arrived.
Embodiment 22
The crystal form C of 45mg De Luogewei sodium salt prepared by embodiment 10 is put into 145 DEG C of baking ovens, keeps 30 at 145 DEG C Minute to solvent is sloughed completely, takes out and is placed at room temperature for get the crystal form D of 38.2mg De Luogewei sodium salt is arrived.
Embodiment 23
The crystal form C of 45mg De Luogewei sodium salt prepared by embodiment 10 is put into 130 DEG C of baking ovens, is kept at 130 DEG C It to solvent is sloughed completely, takes out and is placed at room temperature for get the crystal form D of 38.2mg De Luogewei sodium salt is arrived within 40 minutes.
Sample prepared by embodiment 16~23 has and the same or similar XRPD figure of 15 sample of embodiment, IR figure, PLM Figure, DSC figure, TGA figure and adsorption isothermal curve figure (not shown).Illustrate that 16~23 sample of embodiment with 15 sample of embodiment is phase Same substance.
Embodiment 24
The known De Luogewei sodium salt crystal form I of the preparation of 60mg preparation example 1 is weighed, 5.0ml trifluoroethanol is added, 40 DEG C super Sound makes dissolved clarification 1 times of solubility (the known De Luogewei sodium salt crystal form I of the concentration of the solution in trifluoroethanol), then from So volatilization crystallization 2 days, obtain the crystal form E of 69.0mg De Luogewei sodium salt.
XRPD figure is shown in Figure 33.
PLM figure is shown in Figure 34, is shown as rod shaped particles.
DSC figure is shown in Figure 35.
TGA figure is shown in Figure 36, display: the weightlessness 15.12% before 150 DEG C is roughly equal to containing a molecule trifluoroethanol.
IR figure is shown in Figure 37.
Embodiment 25
The known De Luogewei sodium salt crystal form I of the preparation of 48mg preparation example 1 is weighed, 5.0ml trifluoroethanol: ethyl alcohol is added The mixed solvent of (1:1), 30 DEG C of ultrasounds make dissolved clarification, and (the known De Luogewei sodium salt crystal form I of the concentration of the solution is in the mixing 0.8 times of solubility in solvent), it then volatilizees crystallization 3 days naturally, obtains the crystal form E of 55.2mg De Luogewei sodium salt.
Embodiment 26
The known De Luogewei sodium salt crystal form I of the preparation of 54mg preparation example 1 is weighed, 5.0ml trifluoroethanol: acetic acid second is added The mixed solvent of ester (2:1), 50 DEG C of ultrasounds make dissolved clarification, and (the known De Luogewei sodium salt crystal form I of the concentration of the solution is mixed at this 0.9 times of solubility in bonding solvent), it then volatilizees crystallization 1 day naturally, obtains the crystal form E of 62.1mg De Luogewei sodium salt.
Embodiment 27
The known De Luogewei sodium salt crystal form I of the preparation of 30mg preparation example 1 is weighed, 5.0mL trifluoroethanol: acetonitrile is added The mixed solvent of (1.5:1), 20 DEG C of ultrasounds make dissolved clarification, and (the known De Luogewei sodium salt crystal form I of the concentration of the solution is mixed at this 0.5 times of solubility in bonding solvent), it then volatilizees crystallization 5 days naturally, obtains the crystal form E of 34.5mg De Luogewei sodium salt.
Embodiment 28
The known De Luogewei sodium salt crystal form I of the preparation of 12mg preparation example 1 is weighed, 5.0mL trifluoroethanol: n-butanol is added The mixed solvent of (4:1), 60 DEG C of ultrasounds make dissolved clarification, and (the known De Luogewei sodium salt crystal form I of the concentration of the solution is in the mixing 0.6 times of solubility in solvent), it then volatilizees crystallization 4 days naturally, obtains the crystal form E of 13.8mg De Luogewei sodium salt.
Embodiment 29
48mg De Luogewei sodium salt crystal form D of the invention is weighed, add 5.0mL trifluoroethanol: the mixing of methanol (1:1) is molten Agent, 45 DEG C of ultrasounds make dissolved clarification, and (concentration of solution De Luogewei sodium salt crystal form D of the invention is in the in the mixed solvent solubility 0.7 times), then naturally volatilize crystallization 4 days, obtain the crystal form E of 55.2mg De Luogewei sodium salt.
Embodiment 30
The known De Luogewei sodium salt crystal form I of the preparation of 18mg preparation example 1 is weighed, add 5.0mL trifluoroethanol: acetic acid is different The mixed solvent of propyl ester (1.6:1), 45 DEG C of ultrasounds make dissolved clarification, and (the known De Luogewei sodium salt crystal form I of this concentration is mixed at this 0.3 times of solubility in bonding solvent), it then volatilizees crystallization 5 days naturally, obtains the crystal form E of 20.7mg De Luogewei sodium salt.
Embodiment 31
The known De Luogewei sodium salt crystal form I of the preparation of 60mg preparation example 1 is weighed, 5.0mL trifluoroethanol is added, ultrasound is molten (concentration of the solution is known De Luogewei sodium salt crystal form I 1 times of solubility in trifluoroethanol) clearly, then toward dissolved clarification liquid 1 hour precipitation solid is stirred at room temperature in middle addition 50mL ethyl alcohol, and filtering, filter cake is washed with 3.0mL trifluoroethanol, 30 DEG C of dryings 10 Hour, obtain the crystal form E of 66.3mg De Luogewei sodium salt.
Embodiment 32
54mg De Luogewei sodium salt crystal form A of the invention is weighed, adds 5.0mL trifluoroethanol, ultrasonic dissolved clarification be (solution Concentration is De Luogewei sodium salt crystal form A of the invention 0.9 times of solubility in trifluoroethanol), then it is added into dissolved clarification liquid 2 hours precipitation solids are stirred at room temperature in 60mL ethyl acetate, and filtering, filter cake is washed with 3.0mL trifluoroethanol, and 25 DEG C of dryings 18 are small When, obtain the crystal form E of 58.4mg De Luogewei sodium salt.
Embodiment 33
The known De Luogewei sodium salt amorphous article of the preparation of 48mg preparation example 2 is weighed, 5.0mL trifluoroethanol is added, is surpassed Sound dissolved clarification (concentration of the solution is known De Luogewei sodium salt amorphous article 0.8 times of solubility in trifluoroethanol), so 75mL acetonitrile is added into dissolved clarification liquid afterwards, 5 hours precipitation solids are stirred at room temperature, filters, filter cake is washed with 3.0mL trifluoroethanol, 20 DEG C drying 24 hours, obtain the crystal form E of 51.4mg De Luogewei sodium salt.
Embodiment 34
The known De Luogewei sodium salt crystal form I of the preparation of 30mg preparation example 1 is weighed, 5.0mL trifluoroethanol is added, ultrasound is molten (concentration of the solution is known De Luogewei sodium salt crystal form I 0.5 times of solubility in trifluoroethanol) clearly, then toward dissolved clarification 25mL methanol is added in liquid, 50 DEG C of stirrings, 12 hours precipitation solids filter, and filter cake is washed with 3.0mL trifluoroethanol, 15 DEG C of dryings 28 hours, obtain the crystal form E of 31.8mg De Luogewei sodium salt.
Embodiment 35
The known De Luogewei sodium salt crystal form I of the preparation of 12mg preparation example 1 is weighed, 5.0mL trifluoroethanol is added, ultrasound is molten (concentration of the solution is known De Luogewei sodium salt crystal form I 0.2 times of solubility in trifluoroethanol) clearly, then toward dissolved clarification 100mL n-butanol is added in liquid, 24 hours precipitation solids are stirred at room temperature, filters, filter cake is washed with 3.0mL trifluoroethanol, and 10 DEG C It is 30 hours dry, obtain the crystal form E of 12.4mg De Luogewei sodium salt.
Embodiment 36
The De Luogewei sodium salt crystal form D of the invention of the preparation of 16mg preparation example 1 is weighed, 5.0mL trifluoroethanol, ultrasound are added Dissolved clarification (concentration of the solution is De Luogewei sodium salt crystal form D of the invention 0.4 times of solubility in trifluoroethanol), it is then past 40mL isopropyl acetate is added in dissolved clarification liquid, 40 DEG C of stirrings, 20 hours precipitation solids filter, and filter cake is washed with 3.0mL trifluoroethanol Wash, 5 DEG C drying 48 hours, obtain the crystal form E of 16.4mg De Luogewei sodium salt.
Embodiment 37
48mg De Luogewei sodium salt crystal form A of the invention is weighed, adds 5.0mL trifluoroethanol, ultrasonic dissolved clarification be (solution Concentration is De Luogewei sodium salt crystal form A of the invention 0.8 times of solubility in trifluoroethanol), then it is added into dissolved clarification liquid 13 hours precipitation solids are stirred at room temperature in 75mL toluene, and filtering, filter cake washs with 3.0mL trifluoroethanol, 5 DEG C drying 48 hours, obtain To the crystal form E of 48.1mg De Luogewei sodium salt.
Embodiment 38
The known De Luogewei sodium salt amorphous article of the preparation of 54mg preparation example 2 is weighed, 5.0mL trifluoroethanol is added, is surpassed Sound dissolved clarification (concentration of the solution is known De Luogewei sodium salt amorphous article 0.9 times of solubility in trifluoroethanol), so 65mL isopropyl ether is added into dissolved clarification liquid afterwards, 60 DEG C of stirrings, 16 hours precipitation solids filter, and filter cake is washed with 3.0mL trifluoroethanol Wash, 5 DEG C drying 48 hours, obtain the crystal form E of 51.6mg De Luogewei sodium salt.
Sample prepared by embodiment 25~38 has and the same or similar XRPD figure of 24 sample of embodiment, IR figure, PLM Figure, DSC figure and TGA figure (not shown).Illustrate that 25~38 sample of embodiment and 24 sample of embodiment are identical substances.
Embodiment 39
Prepare the tablet containing De Luogewei sodium salt crystal form A of the invention.
Tablet (the every free alkali of De Luogewei containing 50mg) formula is as follows:
De Luogewei sodium salt crystal form A:52.6mg of the invention
Mannitol: 187.0mg
Povidone: 15.0mg
Sodium carboxymethyl starch: 12.4mg
Microcrystalline cellulose: 30.0mg
Magnesium stearate: 3.0mg
It amounts to: 300.0mg
The preparation step of tablet is as follows:
With 10,000 scales, De Luogewei sodium salt crystal form A of the invention is mixed with mannitol using equal increments method It closes uniformly, then after mixing with microcrystalline cellulose, sodium carboxymethyl starch, povidone, magnesium stearate, is placed in tablet press machine and presses Piece adjusts slice weight to get respective tablets.
Embodiment 40-43
Prepare the tablet of crystal form B respectively containing De Luogewei sodium salt of the present invention, crystal form C, crystal form D and crystal form E.
Each tablet formulation is as follows: the crystal form A of the Sino-German Roger's Wei sodium salt of embodiment 39 being replaced with respectively prepared by the present invention Crystal form B, crystal form C, crystal form D and the crystal form E of De Luogewei sodium salt, wherein the crystal form B, crystal form C, crystal form D and crystal form E match The mole dosage of Fang Zhongde Roger's Wei and De Luogewei sodium salt crystal form A be formulated in it is identical, other components in each formula also with It is identical in embodiment 39.
The preparation step of each tablet is also the same as embodiment 39.
Embodiment 44
The tablet (plain piece) prepared to embodiment 39~43 is coated.
The formula of coating powder is following (every dosage):
Iron oxide yellow: 3.0mg
Polyethylene glycol 8.0mg
Talcum powder 2.0mg
Titanium dioxide 2.0mg
It amounts to: 15.0mg
The operating procedure of coating: tablet (plain piece) prepared by embodiment 39~43 is matched by high-efficiency coating machine with above-mentioned The coating powder that Fang Zufen is mixed with is coated.
Test case 1
For the crystal form A, known De Luogewei sodium salt crystal form I and known De Luogewei of De Luogewei sodium salt of the present invention Sodium salt monohydrate carries out stability competitive assay and compares, the results are shown in Table 1.
The operating process of the stability competitive assay is: taking the De Luogewei sodium salt of the present invention of equivalent (250mg) respectively Crystal form A, preparation example 1 prepare known De Luogewei sodium salt crystal form I and preparation example 3 prepare known De Luogewei sodium salt Monohydrate, mixing are placed in 3mL water, form suspension, after stirring 7 days at room temperature, carry out XRPD characterization.It the results are shown in Table 1.
1 stability competitive assay result of table
As seen from the results in Table 1: by room temperature, the stability competitive assay of magma in water, it is known that De Luogewei sodium Salt crystal form I and known De Luogewei sodium salt monohydrate are changed into De Luogewei sodium salt crystal form A of the invention, and of the invention De Luogewei sodium salt crystal form A keep crystal form it is constant, illustrate De Luogewei sodium salt crystal form A of the invention than known De Luogewei Sodium salt crystal form I and known De Luogewei sodium salt monohydrate are more stable, so that it is 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 form A, crystal form B, crystal form C, crystal form D and the crystal form E of De Luogewei sodium salt prepared by the present invention, comparative sample are taken respectively Known De Luogewei sodium salt crystal form I, De Luogewei sodium salt amorphous article and De Luogewei sodium salt prepared for preparation example 1~3 Monohydrate carries out the comparison that room temperature is lauched middle solubility, hygroscopicity, fusing point, decomposition temperature and granule-morphology.It the results are shown in Table 2.
Solubility detection: taking 50mg sample in 20ml vial, and 15ml deionized water is added, and 26 DEG C are stirred 1 day, sampling It filters and is settled in 5ml volumetric flask, with acetonitrile/water (1:1) constant volume, pass through HPLC detectable concentration.
Decomposition temperature detection: it is detected and is obtained by TGA.
Fusing point detection: it is detected and is obtained by DSC.
Hygroscopicity detection: the weight change within the scope of 20%-80%RH is detected by DVS and is obtained.
Granule-morphology detection: it is detected and is obtained by PLM.
The performance comparison result of the De Luogewei sodium salt of 2 different crystal forms of table
* note: De Luogewei sodium salt amorphous article stirs in water is changed into De Luogewei sodium salt crystal form I for 5 minutes, therefore The apparent solubility of the two is consistent.
By the testing result of table 2 it can be seen that the crystal form A of De Luogewei sodium salt of the invention, relatively known De Luogewei Sodium salt monohydrate, it is less easy to moisture absorption；The crystal form B of De Luogewei sodium salt of the invention and known De Luogewei sodium salt one are hydrated Object compares, and has the advantages such as solubility is high, not easy to moisture absorption, granule-morphology is good；Crystal form C, the crystalline substance of De Luogewei sodium salt of the invention Type D, crystal form E and known De Luogewei sodium salt crystal form I, De Luogewei sodium salt amorphous article and known De Luogewei sodium salt one Hydrate compares, with the high advantage of solubility；The crystal form D of De Luogewei sodium salt of the invention, relatively known De Luogewei sodium Salt crystal form I and De Luogewei sodium salt monohydrate, it is less easy to moisture absorption.
Test case 3
The crystal form A, crystal form B and crystal form D of De Luogewei sodium salt prepared by the present invention are taken respectively, and comparative sample is the system of preparation example 1 Standby known De Luogewei sodium salt crystal form I place under high temperature and humidity illumination condition 10 days stability experiments.High temperature item Part is 80 DEG C, super-humid conditions 90%RH, and illumination condition is 6000lx illumination.HPLC purity of the test sample before and after placement and Largest single impurity content, the results are shown in Table 3.
The stability comparison result of the De Luogewei sodium salt of 3 different crystal forms of table
As shown in Table 3: under conditions of high temperature and humidity illumination 10 days, it is known that De Luogewei sodium salt crystal form I purity reduce 2.8%, largest single impurity content increases 3.1%；And De Luogewei sodium salt crystal form A purity of the invention reduces 0.5%, most Big single miscellaneous content increases 0.1%, and De Luogewei sodium salt crystal form B purity of the invention reduces 0.3%, and largest single impurity content increases Add 0.05%, De Luogewei sodium salt crystal form D purity of the invention reduces 0.4%, and largest single impurity content increases only 0.02%.
Therefore, De Luogewei sodium salt crystal form A of the invention, the stability of crystal form B and crystal form D under high temperature and humidity illumination are bright It is aobvious to be better than known De Luogewei sodium salt crystal form I.
Cited all patent documents and non-patent publications in this specification, are incorporated to this by reference in its entirety Wen Zhong.
The above-mentioned generality to invention involved in the present invention is described and be should not be understood to the description of its specific embodiment For be to the inventive technique scheme constitute limitation.Those skilled in the art's disclosure according to the present invention can not disobeyed Under the premise of invention constituent element involved in carrying on the back, to above-mentioned general description or/and specific embodiment (including embodiment) In public technology feature increased, reduced or combined, formed and belong to other technical solutions of the invention.Of the invention Protection scope should be determined by the scope of protection defined in the claims.

Claims (11)

1. the n-butanol solvent compound crystal form C of structural formula De Luogewei sodium salt as follows,
It is characterized in that, being radiated using Cu-K α, the X-ray powder diffraction collection that the crystal form C is indicated with 2 θ angles is following Position have characteristic peak: 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 °.
2. the n-butanol solvent compound crystal form C of De Luogewei sodium salt according to claim 1, which is characterized in that the crystalline substance The X-ray powder diffraction collection that type C is indicated with 2 θ angles has characteristic peak and relative intensity in following position:
3. the n-butanol solvent compound crystal form C of De Luogewei sodium salt described according to claim 1~any one of 2, feature exist In, the crystal form C FTIR spectrum wave number be 3277,2956,2930,2873,1648,1624,1526,1506, 1428,1283,1251,1087,981,839 and 743cm-1Place has characteristic peak.
4. a kind of preparation side of the n-butanol solvent compound crystal form C of De Luogewei sodium salt according to any one of claims 1 to 3 Method, comprising the following steps: De Luogewei sodium salt is formed into suspension in n-butanol, stirring and crystallizing, by the crystal separation of precipitation, It is dry, obtain the crystal form C；
The temperature of the crystallization is 10~60 DEG C；
The time of the crystallization is 12~48 hours；
The dosage of the Sino-German Roger's Wei sodium salt of suspension be under crystallization temperature its 2~10 times of solubility in n-butanol；
The temperature of the drying is 10~60 DEG C；
The time of the drying is 10~48 hours.
5. the preparation method according to claim 4, which is characterized in that the temperature of the crystallization is 30~50 DEG C.
6. the preparation method according to claim 4, which is characterized in that the time of the crystallization is 12~24 hours.
7. the preparation method according to claim 4, which is characterized in that the dosage of the Sino-German Roger's Wei sodium salt of suspension is It is 2~5 times of solubility in n-butanol under crystallization temperature.
8. the preparation method according to claim 4, which is characterized in that the temperature of the drying is 10~40 DEG C.
9. the preparation method according to claim 4, which is characterized in that the time of the drying is 10~24 hours.
10. a kind of pharmaceutical composition, it includes the active pharmaceutical ingredients for the treatment of and/or prevention effective dose to be selected from claims It is required that the n-butanol solvent compound crystal form C of De Luogewei sodium salt described in any one of 1~3 or making according to claim 4 The n-butanol solvent compound crystal form C for the De Luogewei sodium salt that Preparation Method obtains, and at least one pharmaceutically acceptable carrier Or auxiliary agent.
11. the n-butanol solvent compound crystal form C of De Luogewei sodium salt according to any one of claims 1 to 3 or according to right It is required that the n-butanol solvent compound crystal form C for the De Luogewei sodium salt that 4 preparation methods obtain is in preparation treatment and/or prevention Purposes in the drug of HIV-1 infection.
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CN105121409B (en) 2017-05-24
WO2015139591A1 (en) 2015-09-24
CN106866701A (en) 2017-06-20
CN106831819B (en) 2019-01-04
CN107056813B (en) 2019-07-30
CN106866702B (en) 2019-03-19
CN107056813A (en) 2017-08-18
CN106866702A (en) 2017-06-20
CN106831819A (en) 2017-06-13

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