WO2015139591A1 - 德罗格韦钠盐的晶型及其制备方法 - Google Patents

德罗格韦钠盐的晶型及其制备方法 Download PDF

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WO2015139591A1
WO2015139591A1 PCT/CN2015/074293 CN2015074293W WO2015139591A1 WO 2015139591 A1 WO2015139591 A1 WO 2015139591A1 CN 2015074293 W CN2015074293 W CN 2015074293W WO 2015139591 A1 WO2015139591 A1 WO 2015139591A1
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sodium salt
crystal form
drogvir
preparation
drogove
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PCT/CN2015/074293
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English (en)
French (fr)
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宋小叶
盛晓霞
盛晓红
贾强
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杭州普晒医药科技有限公司
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Priority to CN201580000497.XA priority Critical patent/CN105121409B/zh
Publication of WO2015139591A1 publication Critical patent/WO2015139591A1/zh

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    • 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

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  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystalline form of dragevir sodium salt and a process for the preparation thereof.
  • Droghevir (English name dolutegravir) is a new HIV integrase inhibitor developed by GlaxoSmithKline and Japan's Yanyeyi Pharmaceutical Co., Ltd., which aims to treat AIDS by inhibiting the spread of the virus. It was approved by the US FDA in August 2013 under the trade name TIVICAY, containing Drogove sodium salt, which is a 50 mg oral tablet.
  • the drug is approved for use in a wide range of HIV-infected patients, those who have never received HIV treatment before and who have received anti-HIV treatment, including HIV-infected patients who have previously been treated with other integrase inhibitors.
  • the drug is also approved for use in children 12 years of age and older, at least 40 kg, untreated or treated but not treated with other integrase inhibitors. The recommended dose for these children is 50 mg daily. 1 time.
  • the chemical name of the drogate sodium salt is: (4R, 12aS)-9- ⁇ [(2,4-difluorophenyl)methyl]carbamoyl ⁇ -4-methyl-6,8-dioxo Generation-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine- 7-alcohol sodium salt; English name: dolutegravir sodium or GSK1349572, chemical formula: C 20 H 18 F 2 N 3 NaO 5 ; molecular weight: 441.36; chemical structural formula is as follows:
  • Drogovir and its preparation process are disclosed in the patent documents WO 2010/068253 A1 and WO 2012/018065 A1.
  • WO2010/068253A1 also discloses dragevir sodium salt and its monohydrate, and solid 13 C-NMR, XRPD and IR for drogwevir, dragevir sodium salt and dragevir sodium salt monohydrate The crystal form was characterized.
  • the crystal form of the Droghevir sodium salt disclosed in WO2010/068253A1 is simply referred to as "Form I".
  • Patent document WO 2013/038407 A1 discloses an amorphous form of dragevir sodium salt and a process for its preparation, which are characterized by XRPD, DSC, TGA, FTIR, FT-Raman.
  • the present inventors conducted repeated tests and properties tests on the crystals of Drog's sodium salt Form I, Drogove sodium salt monohydrate and Drogroom sodium salt disclosed in the literature, and the results showed that: Drogg
  • the stability of the sodium salt form I and the delogvir sodium salt monohydrate is not good, and the original crystal form cannot be maintained in the competition experiment of water stability, and their solubility is low and has certain hygroscopicity.
  • Such a property makes the pharmaceutical preparations have problems such as unstable active substance content, poor production reproducibility, increased impurity content during storage, and decreased drug efficacy.
  • the drogvir sodium salt amorphous form is converted to the crystalline form I by stirring in water at room temperature for 5 minutes, and the stability is poor, which is not suitable for solid preparation applications.
  • the invention also relates to a process for the preparation of the novel crystalline form, as well as to pharmaceutical compositions and uses thereof.
  • the new crystalline form has at least one of the following advantageous properties compared to known crystalline forms: good stability, such as crystal form stability, thermal stability, chemical stability, mechanical stability, storage stability, etc.; Good in properties; fast dissolution rate; high crystallinity; not easy to absorb moisture; easy to purify and treat; high chemical purity; low residual solvent; good particle morphology; suitable formulation processability such as good fluidity, favorable powder viscosity, tight Degree and compactability, good appearance; improve bioavailability, formulation efficacy; extend the shelf life of the formulation; suitable for new dosage form applications.
  • the present invention provides Form A of the Drocove sodium salt (referred to simply as "Form A" in the present invention).
  • the crystal form A is an anhydrate of the Drogove sodium salt, and its structural formula is as follows:
  • the X-ray powder diffraction pattern of the crystal form A represented by 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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 °.
  • the X-ray powder diffraction pattern of the crystal form A represented by the 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form A has an X-ray powder diffraction pattern as shown in FIG.
  • the Fourier infrared spectrum of Form A has characteristic peaks at wavenumbers of 2942, 1641, 1537, 1503, 1424, 1321, 1278, 1258, 1094, 1069, 964, 854, 763, and 722 cm -1 .
  • thermogravimetric analysis (TGA) pattern of Form A showed that the sample lost 1.0% of weight before 150 ° C, was an anhydrate, and had a decomposition temperature of 366 ° C.
  • the differential scanning calorimetry (DSC) pattern of Form A shows that it begins to melt decompose at 312 °C.
  • the preparation method of the crystalline form A comprises the steps of: forming a suspension of the known dromevir sodium salt in a mixed solvent of water and an organic solvent, wherein the organic solvent is selected from the group consisting of acetonitrile and 1,4- Dioxane, acetone, methyl ethyl ketone or a mixture thereof, the volume ratio of water to organic solvent is from 3:1 to 5:1, and the crystals are stirred and separated, and the precipitated crystals are separated and dried to obtain the crystal form A.
  • the organic solvent is selected from the group consisting of acetonitrile and 1,4- Dioxane, acetone, methyl ethyl ketone or a mixture thereof, the volume ratio of water to organic solvent is from 3:1 to 5:1, and the crystals are stirred and separated, and the precipitated crystals are separated and dried to obtain the crystal form A.
  • the organic solvent is acetonitrile or 1,4-dioxane.
  • the volume ratio of the water to the organic solvent is from 4:1 to 5:1.
  • the temperature of the crystallization is from 10 to 60 ° C, more preferably from 40 to 60 ° C.
  • the crystallization time is 5 to 14 days, more preferably 5 to 8 days.
  • the amount of the drogvir sodium salt known in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the mixed solvent at the crystallization temperature.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the preparation method of the above crystal form A adopts the crystallization mode of the crystal slurry by stirring a supersaturated solution of the sample (in the presence of insoluble solids) in a solvent to obtain a desired crystal.
  • the known drogvir sodium salt includes various crystal forms or amorphous forms of the disclosed Drogove sodium salt, and includes, for example, but not limited to, according to the patent document WO2010068253A1.
  • Example 11 describes the Derogovir sodium salt Form I prepared by the method, or the Derogovir sodium salt amorphous form prepared according to Method I of Example 1 of Patent Document WO2013038407A1.
  • Form A has the following beneficial properties:
  • Form A was placed in a desiccator at room temperature and relative humidity of 10% to 90% RH for 4 months, and the crystal form and melting point were unchanged.
  • the crystal form A of the present invention has a weight change of 1.0% in the range of 20% to 80% relative humidity compared to the known Rogvir sodium salt monohydrate (the known monohydrate is in the range of 20% to 80%).
  • the change in weight in the relative humidity range was 4.3%), indicating that the crystal form A of the present invention is less hygroscopic.
  • the above properties of the crystalline form A indicate that the crystalline form A of the present invention is stable as compared with the known crystal form I of the drogvir sodium salt and the drogvir sodium salt monohydrate.
  • Form A has better stability in water and is more suitable for solid
  • the wet granulation process of the body preparation or the oral suspension has good processability in the aqueous system; the storage stability of the crystal form A is good, and can adapt to more relaxed environmental conditions of manufacture, storage and transportation,
  • the preparation can better cope with problems such as uneven content of the active ingredient of the drug due to temperature, humidity, crystal form change and the like, and the purity is decreased, thereby reducing the risk of the decrease in the efficacy and the safety risk.
  • the present invention provides a monohydrate crystalline form B of the Drocove sodium salt (referred to simply as "Form B" in the present invention).
  • the crystalline form B is a hydrate of the Drogate sodium salt and contains about 1 mole of water per mole of Form B, the structural formula of which is as follows:
  • the X-ray powder diffraction pattern of Form B expressed in 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form B represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the Form B expressed in 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form B has an X-ray powder diffraction pattern as shown in FIG.
  • the Fourier infrared spectrum of Form B has characteristic peaks at wavenumbers of 2968, 1645, 1537, 1502, 1424, 1320, 1278, 1258, 1095, 1068, 964, 875, 846, 762, and 731 cm -1 .
  • thermogravimetric analysis (TGA) pattern of Form B showed that the sample was a hydrate; the weight loss was 6.2% (containing 2.0% of surface water) before 150 ° C, containing about one molecule of water, and the decomposition temperature was about 369 ° C.
  • the differential scanning calorimetry (DSC) pattern of Form B shows that it begins to melt decompose at 349 °C.
  • the method for preparing the crystalline form B comprises the steps of: forming a suspension of the drogvir sodium salt in a mixed solvent of water and an organic solvent, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, tetrahydrofuran, 1, 4-dioxane, C 3 -C 4 alcohol or a mixture thereof, the volume ratio of water to organic solvent is 1:3 to 1:5, stirring and crystallization, separating the precipitated crystals, and drying at 10 to 30 ° C
  • the crystal form B was obtained in 10 to 48 hours.
  • the C 3 -C 4 alcohol may be n-propanol, isopropanol, n-butanol, sec-butanol or a mixture thereof.
  • the organic solvent is tetrahydrofuran or 1,4-dioxane.
  • the volume ratio of the water to the organic solvent is 1:4 to 1:5.
  • the temperature of the crystallization is from 10 to 60 ° C, more preferably from 30 to 50 ° C.
  • the crystallization time is from 1 to 5 days, more preferably from 1 to 3 days.
  • the amount of the dragevir sodium salt in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in the mixed solvent at the crystallization temperature.
  • the drying temperature is 10 to 20 °C.
  • the drying time is from 10 to 24 hours.
  • the above-mentioned preparation method of the crystal form B employs a crystal crystallization method in which a supersaturated solution of the sample (in the presence of insoluble solids) is stirred in a solvent to obtain a desired crystal.
  • the dragevir sodium salt may include various crystal forms or amorphous forms of the known Drogove sodium salt, including, for example, but not limited to, according to the patent document WO2010068253A1.
  • Form B has the following beneficial properties:
  • the solubility of Form 1 B in water at room temperature was 2.1 mg/mL, which was higher than the solubility of the known dragevir sodium salt monohydrate (which has a solubility in water at room temperature of 1.7 mg/mL).
  • 3 crystal form B has a weight change of only about 0.5% in the range of 20% to 80% relative humidity, relative to the known crystal form of dragevir sodium salt monohydrate (which is in the range of 20% to 80% relative humidity) The change in weight within is about 4.3%), and the known crystal form of Drocove sodium salt (which has a weight change of about 1.1% in the range of 20% to 80% relative humidity) is less hygroscopic.
  • Form 4 B is a rod-shaped particle which is larger than the particles of the known dragevir sodium salt monohydrate.
  • Form B The above properties of Form B indicate that the crystalline form B of the present invention has high solubility and good storage stability as compared with the known crystal form I of Drog's sodium salt or the known drug concentration of Drog's sodium salt monohydrate. It is not easy to absorb moisture and has good particle shape. Its formulation can have higher dissolution and better bioavailability; particle mobility Good, easy to weigh and dump in the production of the preparation, improve the reproducibility of the batch; the stability of the preparation is good, can adapt to the more relaxed environmental conditions of manufacture, storage and transportation, better to resist the environmental temperature, humidity, Factors such as unevenness in the content of active pharmaceutical ingredients and decreased purity may be caused by factors such as light, which may reduce the risk of decreased efficacy and safety risks.
  • the present invention provides n-butanol solvate Form C (abbreviated as "Form C" in the present invention) of the drogvir sodium salt.
  • the crystalline form C is an n-butanol solvate of the drogarevir sodium salt and contains about 1 mole of n-butanol per mole of Form C, the structural formula of which is as follows:
  • the X-ray powder diffraction pattern of the crystal form C expressed in 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form C represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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 °.
  • the X-ray powder diffraction pattern of the Form C expressed in 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • crystalline form C has an X-ray powder diffraction pattern as shown in FIG.
  • the Fourier transform infrared spectrum of the Form C has characteristic peaks at wave numbers of 3277, 2956, 2930, 2873, 1648, 1624, 1526, 1506, 1428, 1283, 1251, 1087, 981, 839, and 743 cm -1 .
  • thermogravimetric analysis (TGA) pattern of Form C showed that the sample had a weight loss of 15.17% before 150 ° C, containing about one molecule of n-butanol, and the decomposition temperature was 367 ° C.
  • a differential scanning calorimetry (DSC) pattern of Form C shows that it begins to melt decompose at 338 °C.
  • the method for preparing the crystalline form C comprises the steps of: forming a suspension of the drogvir sodium salt in n-butanol, stirring and crystallization, separating and crystallizing the precipitated crystal to obtain the crystalline form C.
  • the temperature of the crystallization is from 10 to 60 ° C, more preferably from 30 to 50 ° C.
  • the crystallization time is from 12 to 48 hours, more preferably from 12 to 24 hours.
  • the amount of the dragevir sodium salt in the suspension is from 2 to 10 times, more preferably from 2 to 5 times, the solubility in n-butanol at the crystallization temperature.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the preparation method of the above crystal form C adopts the crystallization mode of the crystal slurry by stirring a supersaturated solution of the sample (in the presence of insoluble solids) in a solvent to obtain a desired crystal.
  • the dragevir sodium salt may include various crystal forms or amorphous forms of the known dragevir sodium salt, and includes, for example, but not limited to, according to the patent document WO2010068253A1.
  • the sodium salt may also include Form A or Form D of the Drogovevir sodium salt of the present invention.
  • Form C has the following beneficial properties:
  • the solubility of Form 1 C in water at room temperature is 4.6 mg/mL, which is higher than the solubility of the known crystal form I of Drogove sodium salt (the solubility in water at room temperature is 2.1 mg/mL).
  • Form C was placed in a desiccator at room temperature and a relative humidity of 10% to 90% RH for 4 months, and the crystal form was unchanged.
  • Form C of the present invention has high solubility and storage stability as compared to the known crystal form I of Drog's sodium salt and the known Drogove sodium salt monohydrate.
  • the formulation can have higher dissolution and better bioavailability, and adapt to more relaxed environmental conditions of manufacture, storage and transportation, and better to resist the uneven content of active pharmaceutical ingredients due to factors such as time and humidity. Problems such as decreased purity reduce the risk of reduced efficacy and safety risks.
  • the present invention provides a crystalline form D of the drogvir sodium salt (referred to simply as "Form D" in the present invention).
  • the crystal form D is an anhydrate of the Drogove sodium salt, and its structural formula is as follows:
  • the X-ray powder diffraction pattern of the crystal form D expressed in 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form D represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form D represented by the 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form D has an X-ray powder diffraction pattern as shown in FIG.
  • the Fourier transform infrared spectrum of the crystal form D has characteristic peaks at wave numbers of 2922, 1636, 1621, 1531, 1504, 1425, 1317, 1280, 1254, 1198, 1110, 964, 858, and 744 cm -1 .
  • thermogravimetric analysis (TGA) pattern of Form D showed a sample decomposition temperature of about 349 °C.
  • a differential scanning calorimetry (DSC) pattern of Form D shows that it begins to melt decompose at 345 °C.
  • the preparation method of the crystal form D adopts any one of the following preparation methods:
  • n-butanol solvate crystal form C of the dragevir sodium salt is heated from room temperature to a desolvation temperature of 150 ° C at a temperature increase rate of 5 to 20 ° C / min, and maintained at 150 ° C for 15 to 35 minutes to complete The solvent was removed, and then cooled to room temperature at a cooling rate of 5 to 20 ° C /min to obtain the crystal form D.
  • the holding time is from 20 to 35 minutes; more preferably from 20 to 30 minutes.
  • the heating rate is 5 to 10 ° C / min.
  • the cooling rate is 10 to 20 ° C / minute.
  • the ambient temperature is between 140 and 150 °C.
  • the time of the placement is 25 to 35 minutes.
  • the preparation method of the above crystal form D employs a crystallization method of high temperature solvent removal.
  • Form D has the following beneficial properties:
  • the solubility of Form 1 in water at room temperature is 4.2 mg/mL, which is higher than the solubility of the known crystal form I of Drogove sodium salt (the solubility in water at room temperature is 2.1 mg/mL).
  • Form D has a weight change of only about 0.1% in the range of 20%-80% relative humidity, relative to the known crystal form of Drogove sodium salt I (its weight change in the range of 20%-80% relative humidity) About 1.1%) and the known dragevir sodium salt monohydrate, which has a weight change of about 4.3% in the range of 20%-80% relative humidity, are less hygroscopic.
  • Form D of the present invention has high solubility and is not hygroscopic, compared to the known crystal form I of Drog's sodium salt and the known Drogove sodium salt monohydrate.
  • Good storage stability It can meet the requirements of solid preparations, has good processability, good batch reproducibility, higher dissolution and better bioavailability, and adapts to more relaxed environmental conditions of manufacturing, storage and transportation. It is good to fight against problems such as uneven content of the active ingredients of the drug and the decrease in purity due to factors such as time and humidity, and reduce the risk of decreased efficacy and safety risks.
  • the present invention provides a trifluoroethanol solvate crystal form E (abbreviated as "Form E” in the present invention) of the Drogate sodium salt.
  • the Form E is a trifluoroethanol solvate of the Drogovevir sodium salt and contains about 1 mole of trifluoroethanol per mole of Form E, the structural formula of which is as follows:
  • the X-ray powder diffraction pattern of the crystal form E expressed in 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the crystal form E represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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 °.
  • the X-ray powder diffraction pattern of the crystal form E represented by the 2 ⁇ angle has characteristic peaks and relative intensities at the following positions:
  • a typical example of the crystal form E has an X-ray powder diffraction pattern as shown at 33.
  • the Fourier infrared spectrum of the Form E has characteristic peaks at wave numbers of 3419, 3076, 1641, 1536, 1503, 1424, 1321, 1282, 1258, 1069, 1023, 963, 763, and 722 cm -1 .
  • thermogravimetric analysis (TGA) pattern of Form E showed that the sample had a weight loss of 15.1% before 150 ° C, and contained about one molecule of trifluoroethanol, which was a trifluoroethanol solvate; the decomposition temperature was 367 ° C.
  • the preparation method of the crystal form E adopts any one of the following preparation methods:
  • the C 1 -C 4 alcohol may be methanol, ethanol, n-propanol, isopropanol, n-butanol or sec-butanol; the C 4 -C 5 ester may be ethyl acetate or isopropyl acetate.
  • the organic solvent is selected from the group consisting of ethanol, ethyl acetate or acetonitrile.
  • the volume ratio of the trifluoroethanol to the organic solvent is from 1:1 to 4:1, more preferably from 1:1 to 2:1.
  • the preparation method has an operating temperature of 20 to 60 ° C, more preferably 30 to 50 ° C.
  • the crystallization time is from 1 to 5 days, more preferably from 1 to 3 days.
  • the concentration of the dragevir sodium salt solution is 0.2 to 1 times, preferably 0.5 to 1 times, more preferably 0.8 to the solubility of the drogvir sodium salt in trifluoroethanol or the mixed solvent. 1 times.
  • the method (1) for preparing the above crystal form E employs a crystallization method of natural volatilization.
  • the specific operation is: placing the clear solution of the sample in an open glass vial, opening or capping, and naturally volatilizing to remove the solvent to obtain crystals.
  • the C 1 -C 4 alcohol may be methanol, ethanol, n-propanol, isopropanol, n-butanol or sec-butanol; the C 4 -C 5 ester may be ethyl acetate or isopropyl acetate.
  • the anti-solvent is selected from the group consisting of ethanol, ethyl acetate or acetonitrile.
  • the volume of the antisolvent is 5 to 20 times, more preferably 10 to 15 times the volume of trifluoroethanol.
  • the temperature of the crystallization is from 10 to 60 ° C, more preferably room temperature.
  • the crystallization time is from 1 to 24 hours, more preferably from 1 to 5 hours.
  • the concentration of the dragevir sodium salt solution is 0.2 to 1 times, more preferably 0.5 to 1 times the solubility of the dragevir sodium salt in trifluoroethanol at the crystallization temperature.
  • the drying temperature is 5 to 30 ° C, more preferably 20 to 30 ° C.
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the preparation method (2) of the above crystal form E employs a crystallization method resistant to solvent recrystallization, in which a sample is dissolved in a good solvent, and an appropriate amount of anti-solvent is added, and crystals are precipitated by using a difference in solubility of the sample in different solvents.
  • the Drogsafe sodium salt may include various crystal forms or amorphous forms of the known Drogove sodium salt, for example, but not limited to, according to the patent document WO2010068253A1.
  • the sodium salt may also include Form A or Form D of the Drogovevir sodium salt of the present invention.
  • Form E has the following beneficial properties:
  • the solubility of Form 1 E in water at room temperature is 3.7 mg/mL, which is higher than the solubility of the known crystal form I of Drogove sodium salt (the solubility in water at room temperature is 2.1 mg/mL).
  • the solubility of Drogove sodium salt monohydrate, which has a solubility in water at room temperature of 1.7 mg/mL, is high, indicating that Form E of the present invention has a higher solubility.
  • the crystal form E was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% RH for 4 months, and the crystal form remained unchanged.
  • Form E has high solubility and storage stability as compared to the known crystal form I of Drog's sodium salt and the known Drogove sodium salt monohydrate.
  • Good advantage The preparation has higher dissolution rate and better bioavailability, and adapts to more relaxed environmental conditions of manufacture, storage and transportation, and better resists the uneven content and purity of the active ingredient of the drug due to factors such as time and humidity. Problems such as decline, reduce the risk of decreased efficacy and safety risks.
  • the "room temperature” means a temperature of about 10 to 30 °C.
  • the “stirring” can be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation” can be accomplished using conventional techniques in the art, such as filtration or centrifugation.
  • the filtration is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the centrifugation is that the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the crystal obtained by the "separation” may be further washed.
  • the solvent used for washing is preferably the same as the solvent used in the crystal preparation method, and the amount of the washing solvent is usually 0.3 to 1 times the volume of the solvent used in the crystal preparation method.
  • the “anhydrous” means that the sample contains no more than 1.5% by weight or not more than 1.0% by weight of water by TGA.
  • the present invention solves the problems of prior art crystal forms by providing crystalline form A, Form B, Form C, Form D and Form E of the novel Dragevir sodium salt, which has been
  • the crystal form has at least one or more beneficial properties compared to, for example, higher solubility, dissolution rate, less polymorphic conversion and/or dehydration, thermal and mechanical stability, low hygroscopicity, better Flowability, compressibility and apparent density, good storage stability, low residual solvents, etc.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument.
  • the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2 is usually allowed.
  • crystal or crystal form of the present invention is pure, unitary, and substantially free of any other crystal form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Less than 5% by weight of other crystal forms, more preferably less than 1% by weight of other crystal forms.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline form A, crystalline form B, and crystal of the delogvir sodium salt of the present invention.
  • the pharmaceutical compositions may also comprise other pharmaceutically acceptable crystalline forms or amorphous forms of the drogarevir sodium salt or crystalline forms of other pharmaceutically acceptable salts of Droglog or an amorph thereof.
  • the pharmaceutical composition comprises one or more additional pharmaceutically active ingredients including, but not limited to, other antiviral drugs, such as anti-HIV drugs such as reverse transcriptase inhibitors and/or proteases having different mechanisms of action Inhibitor.
  • the pharmaceutical composition can be formulated into a suitable pharmaceutical preparation for oral or parenteral administration.
  • Pharmaceutical preparations suitable for oral administration, solid oral dosage forms include, for example, tablets, granules, powders, pills, powders, capsules, and the like, and liquid oral dosage forms include, for example, solutions, syrups, suspensions, emulsions, and the like,
  • the crystalline form of the drogvir sodium salt of the present invention in the suspension is maintained in a solid form.
  • Pharmaceutical preparations suitable for parenteral administration for example, including intravenous drip preparations, intramuscular or subcutaneous injections, rectal suppositories, vaginally administered sprays, pastes, intranasal inhalation preparations or topical
  • a transdermal patch form for administration may be adapted for rapid release, delayed release or modified release of the active ingredient.
  • the pharmaceutically acceptable carrier or adjuvant in the pharmaceutical composition includes, but is not limited to, diluents such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous phosphoric acid.
  • the pharmaceutically acceptable carrier or adjuvant in the pharmaceutical composition comprises a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil , ethanol, propanol, glycerin, etc.
  • a carrier such as polyethylene glycol or polypropylene glycol can also be used.
  • a water or non-aqueous sterile solution injection may contain a buffer, an antioxidant, a bacteriostatic agent, and a solute capable of making the pharmaceutical composition isotonic with blood, water or non-aqueous.
  • the bacterial suspension may contain a suspending agent and a thickening agent.
  • Each carrier or adjuvant must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art. Preparation of drug groups
  • the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D or the crystalline form E of the drogvir sodium salt of the present invention is mixed with one or more pharmaceutically acceptable carriers or adjuvants.
  • admixed with one or more other pharmaceutically active ingredients can be prepared.
  • the solid preparation can be prepared by a process such as mixing, granulation, or the like.
  • Liquid preparations can be prepared by processes such as dissolution, dispersion, emulsification, and the like.
  • the crystalline form A, crystalline form B, crystalline form C, crystalline form D or crystalline form E of the drogvir sodium salt of the present invention has a significant inhibitory effect on the integrase of the virus, as a retrovirus (including HIV-1, HIV). Integrase inhibitors of -2, HTLV-1, SIV-1, FIV-1), in particular for the preparation of a medicament for the treatment and/or prevention of HIV infection.
  • the present invention provides a method of treating and/or preventing HIV-1 infection, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a crystalline form selected from the group consisting of the drogvir sodium salt of the present invention.
  • a crystalline form selected from the group consisting of the drogvir sodium salt of the present invention.
  • Different doses are used depending on the method of administration, the age, weight and condition of the patient.
  • about 0.1 mg to 1000 mg per day is administered per adult; in the case of parenteral administration, about 0.05 mg to 500 mg per day is administered per adult.
  • Figure 1 is an XRPD pattern of a known crystalline form I of Drogovir sodium salt prepared in Preparation Example 1.
  • Figure 3 is a graph showing the isothermal adsorption curve of the known crystal form I of Drocove sodium salt prepared in Preparation Example 1.
  • Figure 5 is an XRPD pattern of the known drogvir sodium salt amorphous form prepared in Preparation Example 2.
  • Figure 6 is an XRPD pattern of the known dragevir sodium salt monohydrate prepared in Preparation Example 3.
  • Figure 7 is a PLM diagram of the known dragevir sodium salt monohydrate prepared in Preparation Example 3.
  • Figure 8 is a graph showing the isothermal adsorption curve of the known dragevir sodium salt monohydrate prepared in Preparation Example 3.
  • Figure 9 is an IR chart of the known dragevir sodium salt monohydrate prepared in Preparation Example 3.
  • Figure 10 is an XRPD pattern of Form A of the Drocove sodium salt of the present invention.
  • Figure 11 is a PLM diagram of Form A of the Drocove sodium salt of the present invention.
  • Figure 12 is a DSC chart of Form A of the Drocove sodium salt of the present invention.
  • Figure 13 is a TGA diagram of Form A of the Drocove sodium salt of the present invention.
  • Figure 14 is a graph showing the isothermal adsorption profile of Form A of the Drogvir sodium salt of the present invention.
  • Figure 15 is an IR chart of Form A of the Drocove sodium salt of the present invention.
  • Figure 16 is an XRPD pattern of Form B of the Drocove sodium salt of the present invention.
  • Figure 17 is a PLM diagram of Form B of the Drocove sodium salt of the present invention.
  • Figure 18 is a DSC chart of Form B of the Drocove sodium salt of the present invention.
  • Figure 19 is a TGA diagram of Form B of the Drocove sodium salt of the present invention.
  • Figure 20 is a graph showing the isothermal adsorption curve of Form B of the Drocove sodium salt of the present invention.
  • Figure 21 is an IR chart of Form B of the Drocove sodium salt of the present invention.
  • Figure 22 is an XRPD pattern of Form C of the Drocove sodium salt of the present invention.
  • Figure 23 is a PLM diagram of Form C of the Drocove sodium salt of the present invention.
  • Figure 24 is a DSC chart of Form C of the Drocove sodium salt of the present invention.
  • Figure 25 is a TGA diagram of Form C of the Drocove sodium salt of the present invention.
  • Figure 26 is an IR chart of Form C of the Drocove sodium salt of the present invention.
  • Figure 27 is an XRPD pattern of Form D of the Drocove sodium salt of the present invention.
  • Figure 28 is a PLM diagram of Form D of the Drocove sodium salt of the present invention.
  • Figure 29 is a DSC chart of Form D of the Drocove sodium salt of the present invention.
  • Figure 30 is a TGA diagram of Form D of the Drocove sodium salt of the present invention.
  • Figure 31 is a graph showing the isothermal adsorption curve of Form D of the Drocove sodium salt of the present invention.
  • Figure 32 is an IR chart of Form D of the Drocove sodium salt of the present invention.
  • Figure 33 is an XRPD pattern of Form E of the Drocove sodium salt of the present invention.
  • Figure 34 is a PLM diagram of Form E of the Drocove sodium salt of the present invention.
  • Figure 35 is a DSC chart of Form E of Drocove sodium salt of the present invention.
  • Figure 36 is a TGA diagram of Form E of the Drocove sodium salt of the present invention.
  • Figure 37 is an IR chart of Form E of Drocove sodium salt of the present invention.
  • X-ray powder diffraction (XPRD): The instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer at 40 kV and 40 mA, a Mo color Instrument, Lynxeye detector. The instrument is calibrated with the standard (usually corundum) supplied with the instrument before use. The sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate. The detailed detection conditions are as follows, the angle range is 3 - 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • the polarized light microscope (PLM) image was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover slip, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture.
  • PLM polarized light microscope
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 1 to 10 mg is usually placed in an aluminum pan, and the sample is raised from 0 ° C to 375 ° C or 400 ° C under the protection of 40 mL / min dry nitrogen at a temperature increase rate of 10 ° C / min.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 400 ° C or 450 by a stepwise high-resolution detection method at a heating rate of 10 ° C / min under the protection of 40 mL / min dry nitrogen. °C.
  • Isothermal adsorption curve The data was taken from the TA Instruments Q5000TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually 1 to 10 mg of the sample is placed in a platinum crucible, and the TA software records the sample during the relative humidity change from 0% to 80% to 0%. The weight changes. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.
  • Infrared spectroscopy (IR) data is taken from BrukerTensor 27, instrument control software and data analysis software are OPUS, usually using ATR equipment, infrared absorption spectrum is collected in the range of 600-4000 cm -1 , scanning time of sample and blank background are both For 16 seconds, the instrument resolution is 4cm -1 .
  • High-performance liquid phase analysis (HPLC) data was taken from Agilent 1260, instrument control software was Agilent ChemStation B.04 online, and analysis software was Agilent ChemStation B.04 offline.
  • instrument control software was Agilent ChemStation B.04 online
  • analysis software was Agilent ChemStation B.04 offline.
  • C18 column 250mm * 4.6mm, column temperature 35 ° C, wavelength 254nm, flow rate 0.7mL / min, injection volume 20 ⁇ L, running time 30 minutes.
  • the mobile phase A contained 0.01 mol/L potassium dihydrogen phosphate
  • the mobile phase B was acetonitrile
  • the mobile phase A: mobile phase B 55:45.
  • the temperature in the examples is room temperature unless otherwise specified.
  • the ratio of the components in the mixed solvent is, for example, a volume ratio unless otherwise specified.
  • the ultrasonic operation in the examples can promote dissolution of the sample, and the apparatus is an ultrasonic cleaner, which is performed at 40 kHz for 5 minutes.
  • the known crystal form I of the Drogove sodium salt can be prepared according to the method described in Example 11 of the patent document WO2010/068253A1.
  • the specific preparation method is as follows: 12.0 g of drogvir is dissolved in 36 mL of ethanol by heating, 14.5 mL of 2N aqueous NaOH solution is added to the solution at 80 ° C, the solution is gradually cooled to room temperature, filtered, and 50 mL of ethanol is used. It was washed and dried at 50 ° C to obtain a dragevir sodium salt.
  • the XRPD pattern is shown in Figure 1 and shows the crystal form I of the drogvir sodium salt disclosed in the patent document WO 2010/068253 A1.
  • the PLM map is shown in Figure 2 and is shown as smaller, rod-shaped particles.
  • the isotherm adsorption curve is shown in Figure 3, which shows a weight change of 1.1% in the range of 20%-80% relative humidity.
  • the IR chart is shown in Figure 4, which shows the crystal form I of the drogvir sodium salt disclosed in the patent document WO 2010/068253 A1.
  • the known dromevir sodium salt amorphous form can be prepared by referring to Method I of Example 1 of Patent Document WO2013/038407A1.
  • the XRPD pattern is shown in Figure 5, showing no characteristic peaks and is amorphous.
  • the known drogvir sodium salt monohydrate can be prepared according to the method described in Example 1m of the patent document WO2010/068253A1.
  • the specific preparation method is as follows: 10 g of drogvir sodium salt is dissolved in 200 mL of tetrahydrofuran-water (4:1) solution at 30 ° C, and 12 mL of 2N NaOH aqueous solution is further added. The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with 100 mL of tetrahydrofuran-water (4:1) solution and 100 mL of tetrahydrofuran, and dried at 85 ° C to give Drogvir sodium salt monohydrate.
  • the PLM map is shown in Figure 7 and is shown as small particles.
  • the isothermal adsorption curve is shown in Figure 8, which shows a weight change of 4.3% in the range of 20%-80% relative humidity.
  • the IR chart is shown in Figure 9, which shows the monohydrate crystal form of the Drogate sodium salt disclosed in the patent document WO 2010/068253 A1.
  • the PLM map is shown in Figure 11, which shows: small, irregular particles.
  • the DSC chart is shown in Figure 12.
  • the TGA plot is shown in Figure 13, which shows that the weight loss was 1.0% before 150 ° C and was an anhydrate.
  • the isotherm adsorption curve is shown in Figure 14, which shows a weight change of 1.0% in the range of 20%-80% relative humidity.
  • the IR chart is shown in Figure 15.
  • the samples prepared in Examples 2 to 4 had the same or similar XRPD patterns, IR patterns, PLM patterns, DSC patterns, TGA patterns, and isothermal adsorption patterns (not shown) as the samples of Example 1.
  • the samples of Examples 2 to 4 were identical to the samples of Example 1.
  • Dro in the suspension weigh 60 mg of the known Drocovir sodium salt Form I prepared in Preparation Example 1, and add 5.0 mL of a mixed solvent of water:tetrahydrofuran (1:4) to form a suspension (known as Dro in the suspension).
  • the amount of the crystal form I of the Gewei sodium salt is twice the solubility in the mixed solvent at the crystallization temperature, and the suspension is stirred at 60 ° C for 1 day, filtered, and the filter cake is treated with 2.0 mL of water: tetrahydrofuran ( The mixed solvent of 1:4) was washed and vacuum dried at 10 ° C for 24 hours to obtain crystal form B of 58.7 mg of drocove sodium salt.
  • the PLM map is shown in Figure 17, which shows: rod-shaped particles.
  • the DSC chart is shown in Figure 18.
  • the TGA chart is shown in Figure 19, showing a weight loss of 6.2% (containing 2.0% of surface water) before 150 °C, containing about one molecule of water.
  • the isotherm adsorption curve is shown in Figure 20. It shows that the weight change in the range of 20%-80% relative humidity is 0.5%, indicating that it is not easy to absorb moisture.
  • the IR chart is shown in Figure 21.
  • Drocovir sodium salt Form I prepared in Preparation Example 1, and add a mixed solvent of 5.0 mL of water: dimethyl sulfoxide (1:3) to form a suspension (known in the suspension).
  • the amount of the Drogove sodium salt crystal form I is 5 times that of the mixed solvent in the mixed solvent at the crystallization temperature, and the suspension is stirred at 20 ° C for 4 days, filtered, and the filter cake is 3.0 mL of water.
  • a mixed solvent of dimethyl sulfoxide (1:3) was washed and dried at 18 ° C for 12 hours to obtain 28.0 mg of the crystalline form B of the drocove sodium salt.
  • the samples prepared in Examples 6 to 9 had the same or similar XRPD patterns, IR patterns, and samples as in Example 5. PLM map, DSC map, TGA map, and isothermal adsorption curve (not shown). The samples of Examples 6 to 9 are identical to the samples of Example 5.
  • the PLM map is shown in Figure 23 and is shown as small particles.
  • the DSC chart is shown in Figure 24.
  • the TGA map is shown in Figure 25, showing a weight loss of 15.2% before 150 °C, containing about one molecule of n-butanol.
  • the IR chart is shown in Figure 26.
  • drogvir sodium salt amorphous form prepared in Preparation Example 2 250 mg was weighed, and 5.0 mL of n-butanol solvent was added to form a suspension (the drogvir sodium salt amorphous substance was known in the suspension). The dosage is 10 times of the solubility in n-butanol at the crystallization temperature. The suspension is stirred at 10 ° C for 48 hours, filtered, and the filter cake is washed with 3.0 mL of n-butanol and dried at 60 ° C for 28 hours to obtain 244.7. Form C of mg drogvir sodium salt.
  • the samples prepared in Examples 11 to 14 had the same or similar XRPD patterns, IR patterns, PLM patterns, DSC patterns, and TGA patterns (not shown) as the samples of Example 10.
  • the samples of Examples 11 to 14 were identical to the samples of Example 10.
  • Form C of 20 mg of drogvir sodium salt prepared in Example 10 was heated from room temperature to 150 ° C at 10 ° C / min, held at 150 ° C for 30 minutes to completely remove the solvent, and then cooled to 10 ° C / min to At room temperature, crystal form D of 16.9 mg of drocove sodium salt was obtained.
  • the PLM map is shown in Figure 28, which shows: small particles.
  • the DSC chart is shown in Figure 29.
  • the TGA diagram is shown in Figure 30.
  • the isotherm adsorption curve is shown in Figure 31, showing a weight change of 0.06% in the range of 20% to 80% relative humidity.
  • the IR chart is shown in Figure 32.
  • Form C of 30 mg of drogvir sodium salt prepared in Example 10 was heated to 150 ° C at 8 ° C / min, held at 150 ° C for 25 minutes until the solvent was completely removed, and then cooled to room temperature at 15 ° C / min, ie Form 2 of 25.4 mg of drocove sodium salt was obtained.
  • Form 50 of 50 mg of drogvir sodium salt prepared in Example 10 was heated to 150 ° C at 5 ° C / min, held at 150 ° C for 20 minutes to completely remove the solvent, and then cooled to room temperature at 20 ° C / min, ie Form D of 42.4 mg of drocove sodium salt was obtained.
  • Form C of 28 mg of drogvir sodium salt prepared in Example 10 was heated to 150 ° C at 15 ° C / min, held at 150 ° C for 33 minutes to completely remove the solvent, and then cooled to room temperature at 8 ° C / min, ie The crystal form D of 23.8 mg of drocove sodium salt was obtained.
  • Form C of 26 mg of drogvir sodium salt prepared in Example 10 was heated to 150 ° C at 20 ° C / min, held at 150 ° C for 35 minutes until the solvent was completely removed, and then cooled to room temperature at 5 ° C / min, ie The crystalline form D of 22.1 mg of drocove sodium salt was obtained.
  • Form 30 of 30 mg of drogvir sodium salt prepared in Example 10 was placed in a 140 ° C oven for 35 minutes until the solvent was completely removed, and taken out at room temperature to obtain a crystal form of 25.4 mg of drocove sodium salt. D.
  • Form 50 of 50 mg of drogvir sodium salt prepared in Example 10 was placed in an oven at 150 ° C, held at 150 ° C for 25 minutes until the solvent was completely removed, and taken out at room temperature to obtain 42.4 mg of drocove sodium salt.
  • Form D Form 50 of 50 mg of drogvir sodium salt prepared in Example 10 was placed in an oven at 150 ° C, held at 150 ° C for 25 minutes until the solvent was completely removed, and taken out at room temperature to obtain 42.4 mg of drocove sodium salt.
  • Form 45 of 45 mg of drogvir sodium salt prepared in Example 10 was placed in an oven at 145 ° C, held at 145 ° C for 30 minutes until the solvent was completely removed, and taken out at room temperature to obtain 38.2 mg of drocove sodium salt.
  • Form D Form 45 of 45 mg of drogvir sodium salt prepared in Example 10 was placed in an oven at 145 ° C, held at 145 ° C for 30 minutes until the solvent was completely removed, and taken out at room temperature to obtain 38.2 mg of drocove sodium salt.
  • Form 45 of 45 mg of drogvir sodium salt prepared in Example 10 was placed in an oven at 130 ° C, held at 130 ° C for 40 minutes until the solvent was completely removed, and taken out at room temperature to obtain 38.2 mg of drocove sodium. Form D of the salt.
  • the samples prepared in Examples 16 to 23 had the same or similar XRPD patterns, IR patterns, PLM patterns, DSC patterns, TGA patterns, and isothermal adsorption patterns (not shown) as the samples of Example 15. DESCRIPTION OF EMBODIMENTS 16 to 23 The sample was the same as the sample of Example 15.
  • Drocovir sodium salt Form I prepared in Preparation Example 1, add 5.0 ml of trifluoroethanol, and dissolve it by ultrasonication at 40 ° C (the concentration of this solution is known as Drocove sodium salt crystal).
  • Form I was 1 times more soluble in trifluoroethanol) and then naturally devitrified for 2 days to give crystal form E of 69.0 mg of drocove sodium salt.
  • the PLM map is shown in Figure 34 and is shown as rod-shaped particles.
  • the DSC chart is shown in Figure 35.
  • the TGA chart is shown in Figure 36, showing a weight loss of 15.12% before 150 ° C, containing about one molecule of trifluoroethanol.
  • the IR chart is shown in Figure 37.
  • Drogeve sodium salt crystal form D of the present invention add 5.0 mL of a mixed solvent of trifluoroethanol:methanol (1:1), and dissolve it by ultrasonication at 45 ° C (the concentration of the solution is the Dro of the invention)
  • the Gwee sodium salt crystal form D was 0.7 times more soluble in the mixed solvent, and then naturally devitrified for 4 days to obtain 55.2 mg of the crystal form E of the dragevir sodium salt.
  • Drocove sodium salt form I prepared in Preparation Example 1, add 5.0 mL of trifluoroethanol, and dissolve it by ultrasonication (the concentration of the solution is known as the crystal form of the Derogovir sodium salt). 5 times the solubility in trifluoroethanol, then 50 mL of ethanol was added to the supernatant, and the mixture was stirred at room temperature for 1 hour to precipitate a solid, which was filtered, and the filter cake was washed with 3.0 mL of trifluoroethanol, and dried at 30 ° C for 10 hours to obtain 66.3 mg of Dro Form E of the Gwee sodium salt.
  • Drocovir sodium salt Form I prepared in Preparation Example 1, add 5.0 mL of trifluoroethanol, and dissolve it by ultrasonication (the concentration of the solution is known as the crystal form of Drogvir sodium salt). 0.2 times of solubility in trifluoroethanol, and then 100 mL of n-butanol was added to the supernatant, and the mixture was stirred at room temperature for 24 hours to precipitate a solid, which was filtered, and the filter cake was washed with 3.0 mL of trifluoroethanol and dried at 10 ° C for 30 hours to obtain 12.4 mg.
  • Form E of Drogove sodium salt Form E of Drogove sodium salt.
  • a tablet containing the crystal form A of the dragevir sodium salt of the present invention is prepared.
  • the tablets (50 mg of drocovir free base per tablet) are formulated as follows:
  • the preparation steps of the tablet are as follows:
  • the dextrovir sodium salt form A of the present invention is uniformly mixed with mannitol by an equal amount of 10,000 tablets, and then combined with microcrystalline cellulose, sodium carboxymethyl starch, povidone, and stearic acid. After the magnesium silicate is uniformly mixed, it is placed in a tableting machine to be tableted, and the tablet weight is adjusted to obtain a corresponding tablet.
  • Each tablet formulation was as follows: the crystalline form A of the dragevir sodium salt in Example 39 was replaced with the crystalline form B, crystalline form C, crystalline form D and crystalline form E of the delogvir sodium salt prepared in the present invention, respectively.
  • the dosage of the crystalline form B, the crystalline form C, the crystalline form D and the crystalline form E is the same as that of the drogvir sodium salt form A formulation, and the other in each formulation
  • the composition was also the same as in Example 39.
  • the tablets (primary tablets) prepared in Examples 39 to 43 were coated.
  • the formula of the coating powder is as follows (the amount of each tablet):
  • Titanium dioxide 2.0mg
  • the crystal form A, the crystal form B, the crystal form C, the crystal form D and the crystal form E of the drogvir sodium salt prepared by the present invention were respectively taken, and the comparative samples were the known drrogweed prepared in the preparation examples 1 to 3.
  • Sodium salt crystal form I, drogvir sodium salt amorphous form and dragevir sodium salt monohydrate were compared at room temperature for solubility, hygroscopicity, melting point, decomposition temperature and particle morphology. The results are shown in Table 2.
  • Solubility test Take 50mg sample in 20ml glass bottle, add 15ml deionized water, stir at 26°C for 1 day, sample and filter and dilute to 5ml volumetric flask, dilute to volume with acetonitrile/water (1:1), and pass HPLC. concentration.
  • Decomposition temperature detection obtained by TGA detection.
  • Hygroscopicity detection Obtained by DVS detecting weight changes in the range of 20%-80% RH.
  • Particle morphology detection obtained by PLM detection.
  • the crystal form A of the Drogove sodium salt of the present invention is less hygroscopic than the known Drogove sodium salt monohydrate; the delogvir sodium of the present invention
  • the crystal form B of the salt has the advantages of high solubility, low moisture absorption, good particle morphology, etc.
  • the crystal form C and crystal form of the delogvir sodium salt of the present invention D, crystal form E and known drogvir sodium salt crystal form I, drogvir sodium salt amorphous form and known dragevir sodium salt monohydrate have the advantage of high solubility;
  • the crystalline form D of the inventive dragevir sodium salt is less hygroscopic than the known dragevir sodium salt form I and dragevir sodium salt monohydrate.

Abstract

本发明涉及德罗格韦钠盐的新晶型。相比德罗格韦钠盐的已知晶型，本发明的新晶型具有一种或多种的有益性质，例如水中稳定性好、溶解度高、不易吸湿、贮存稳定性好、颗粒形貌佳。本发明还涉及所述德罗格韦钠盐新晶型的制备方法、其药物组合物及其用于制备治疗和/或预防HIV-1感染的药物中的用途。

Description

德罗格韦钠盐的晶型及其制备方法 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及德罗格韦钠盐的晶型及其制备方法。
背景技术
德罗格韦(英文名称dolutegravir)是葛兰素史克制药公司同日本盐野义制药公司携手研发的一种新型HIV整合酶抑制剂，该抑制剂旨在通过抑制病毒的扩散从而治疗艾滋病。其于2013年8月获美国FDA批准上市，商品名TIVICAY，含德罗格韦钠盐，为50mg口服片剂。该药获准用于HIV感染的广泛人群，即以前从未接受过HIV治疗以及接受过抗HIV治疗的感染患者，包括之前已用过其他整合酶抑制剂治疗的HIV感染患者均可应用。该药还被批准用于年龄12岁及以上、体重至少40公斤、未治疗过或经过治疗但未曾接受过其他整合酶抑制剂治疗的儿童，对上述儿童患者的推荐剂量是50mg，口服每日1次。
德罗格韦钠盐的化学名称为：(4R,12aS)-9-{[(2,4-二氟苯基)甲基]氨基甲酰基}-4-甲基-6,8-二氧代-3,4,6,8,12,12a-六氢-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]噁嗪-7-醇钠盐；英文名称为：dolutegravir sodium或GSK1349572，化学式为：C20H18F2N3NaO5；分子量为：441.36；化学结构式如下所示：
Figure PCTCN2015074293-appb-000001
专利文献WO2010/068253A1和WO2012/018065A1公开了德罗格韦及其制备方法。WO2010/068253A1还公开了德罗格韦钠盐及其一水合物，并用固态13C-NMR、XRPD和IR对德罗格韦、德罗格韦钠盐及德罗格韦钠盐一水合物的晶型进行了表征。为便于区分，本发明中将WO2010/068253A1公开的德罗格韦钠盐的晶型简称为“晶型I”。
专利文献WO2013/038407A1公开了德罗格韦钠盐的无定型物及其制备方法，并用XRPD、DSC、TGA、FTIR、FT-Raman对其进行了表征。
本发明人对文献公开的德罗格韦钠盐晶型I、德罗格韦钠盐一水合物以及德罗格韦钠盐无定型物进行了重复试验及性质检测，结果显示：德罗格韦钠盐晶型I和德罗格韦钠盐一水合物的稳定性不好，在水中稳定性竞争实验中不能维持原有的结晶形态，并且它们的溶解性偏低、具有一定的吸湿性，这样的性质使得其药物制剂存在活性物质含量不稳定、生产重现性差、贮存过程中杂质含量增加、药效下降等问题。此外，德罗格韦钠盐无定型物在水中、室温下搅拌5分钟即转变为晶型I，稳定性很差，不适合固体制剂应用。
为了满足药物制剂对于药物活性成分形态的严格要求，扩大制剂开发所选 用的原料形态，本领域仍需要开发德罗格韦钠盐的新晶型。
发明内容
针对现有技术的不足，本发明的目的是通过提供德罗格韦钠盐的新晶型，解决已知晶型存在的问题。同时，本发明还涉及所述新晶型的制备方法、及其药物组合物和用途。
所述新晶型与已知晶型相比，具有至少一种如下的有利性质：稳定性好，例如晶型稳定性、热学稳定性、化学稳定性、机械稳定性、贮存稳定性等；溶解性好；溶出速度快；结晶度高；不易吸湿；易于纯化和处理；化学纯度高；低残留溶剂；颗粒形貌佳；适宜的制剂可加工性例如流动性好、有利的粉体粘度、紧密度和可压实性、表观好；改善生物利用度、制剂药效；延长制剂保存期；适合新剂型应用等方面。
根据本发明的目的，本发明提供德罗格韦钠盐的晶型A(在本发明中简称为“晶型A”)。
所述晶型A为德罗格韦钠盐的无水物，其结构式如下所示：
Figure PCTCN2015074293-appb-000002
使用Cu-Kα辐射，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、9.0±0.2°、9.3±0.2°、13.9±0.2°、19.2±0.2°和21.8±0.2°。
优选地，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和28.7±0.2°。
更优选地，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
Figure PCTCN2015074293-appb-000003
非限制性地，所述晶型A的一个典型实例具有如图10所示的X-射线粉末衍射图。
所述晶型A的傅里叶红外光谱在波数为2942、1641、1537、1503、1424、1321、1278、1258、1094、1069、964、854、763和722cm-1处具有特征峰。
所述晶型A的热重分析(TGA)图谱显示：样品在150℃之前失重1.0％，为无水物，分解温度为366℃。
所述晶型A的差式扫描量热(DSC)图显示：其在312℃开始熔融分解。
所述晶型A的制备方法，包括以下步骤：将已知的德罗格韦钠盐在水与有机溶剂的混合溶剂中形成混悬液，其中所述有机溶剂选自乙腈、1,4-二氧六环、丙酮、丁酮或其混合物，水与有机溶剂的体积比为3:1～5:1，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型A。
优选地，所述有机溶剂为乙腈或1,4-二氧六环。
优选地，所述水与有机溶剂的体积比为4:1～5:1。
优选地，所述析晶的温度为10～60℃，更优选为40～60℃。
优选地，所述析晶的时间为5～14天，更优选为5～8天。
优选地，所述混悬液中已知的德罗格韦钠盐的用量为析晶温度下其在所述混合溶剂中溶解度的2～10倍，更优选为2～5倍。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
上述晶型A的制备方法采用了晶浆的结晶方式，是将样品的过饱和溶液(有不溶解固体存在)在溶剂中搅拌，得到所需晶体。
上述晶型A的制备方法中，所述已知的德罗格韦钠盐，包括已公开的德罗格韦钠盐的各种晶型或无定型物，例如包括但不限于根据专利文献WO2010068253A1实施例1l描述方法制备的德罗格韦钠盐晶型I，或根据专利文献WO2013038407A1实施例1的3.1方法I制备的德罗格韦钠盐无定型物。
晶型A具有以下的有益性质：
①通过在水中晶浆的稳定性竞争实验对比，已知的德罗格韦钠盐晶型I及德罗格韦钠盐一水合物不能维持原有的结晶形态，均转变成晶型A，而晶型A在同样实验条件下保持晶型不变。
②晶型A在室温、相对湿度10％～90％RH的干燥器中放置4个月，晶型和熔点都不变。
③晶型A在80℃-90％RH-6000lx的高温高湿光照条件下贮存10天后，其纯度的下降和最大单杂含量的增长都明显低于已知的德罗格韦钠盐晶型I的数据，说明其稳定性较已知的德罗格韦钠盐晶型I好。
④与已知的罗格韦钠盐一水合物相比，本发明的晶型A在20％-80％相对湿度范围内重量变化为1.0％(已知的一水合物在20％-80％相对湿度范围内重量变化为4.3％)，说明本发明的晶型A更不易吸湿。
晶型A的上述性质表明：与已知的德罗格韦钠盐晶型I及德罗格韦钠盐一水合物相比，本发明的晶型A稳定性好。晶型A在水中具有更好的稳定性，更适合固 体制剂的湿法制粒工艺或制成口服混悬液，在含水体系中具有良好的制剂可加工性；晶型A的贮存稳定性好，可适应更宽松的制造、贮存和运输的环境条件，其制剂能够更好地对抗由于温度、湿度、晶型变化等因素可能产生的药物活性成分含量不均匀、纯度下降等问题，降低由此带来的疗效下降风险和安全风险。
根据本发明的目的，本发明提供德罗格韦钠盐的一水合物晶型B(在本发明中简称为“晶型B”)。
所述晶型B为德罗格韦钠盐的水合物，且每摩尔晶型B含有约1摩尔水，其结构式如下所示：
Figure PCTCN2015074293-appb-000004
使用Cu-Kα辐射，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：7.9±0.2°、9.0±0.2°、11.1±0.2°、15.1±0.2°、15.9±0.2°和22.4±0.2°。
优选地，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和26.3±0.2°。
更优选地，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
Figure PCTCN2015074293-appb-000005
非限制性地，所述晶型B的一个典型实例具有如图16所示的X-射线粉末衍射图。
所述晶型B的傅里叶红外光谱在波数为2968、1645、1537、1502、1424、1320、1278、1258、1095、1068、964、875、846、762和731cm-1处具有特征峰。
所述晶型B的热重分析(TGA)图谱显示：样品为水合物；在150℃之前失重6.2％(含表面水2.0％)，约合含一分子水，分解温度约为369℃。
所述晶型B的差式扫描量热(DSC)图显示：其在349℃开始熔融分解。
所述晶型B的制备方法，包括以下步骤：将德罗格韦钠盐在水与有机溶剂的混合溶剂中形成混悬液，其中所述有机溶剂选自二甲亚砜、四氢呋喃、1,4-二氧六环、C3～C4醇或其混合物，水与有机溶剂的体积比为1:3～1:5，搅拌析晶，将析出的晶体分离，在10～30℃下干燥10～48小时，得到所述晶型B。
所述C3～C4醇可以是正丙醇、异丙醇、正丁醇、仲丁醇或其混合物。
优选地，所述有机溶剂为四氢呋喃或1,4-二氧六环。
优选地，所述水与有机溶剂的体积比为1:4～1:5。
优选地，所述析晶的温度为10～60℃，更优选为30～50℃。
优选地，所述析晶的时间为1～5天，更优选为1～3天。
优选地，所述混悬液中德罗格韦钠盐的用量为析晶温度下其在所述混合溶剂中溶解度的2～10倍，更优选为2～5倍。
优选地，所述干燥的温度为10～20℃。
优选地，所述干燥的时间为10～24小时。
上述晶型B的制备方法采用了晶浆的结晶方式，是将样品的过饱和溶液(有不溶解固体存在)在溶剂中搅拌，得到所需晶体。
上述晶型B的制备方法中：所述德罗格韦钠盐可以包括已知的德罗格韦钠盐的各种晶型或无定型物，例如包括但不限于根据专利文献WO2010068253A1实施例1l描述方法制备的已知的德罗格韦钠盐晶型I或根据专利文献WO2013038407A1实施例1的3.1方法I制备的已知的德罗格韦钠盐的无定型物；所述德罗格韦钠盐还可以包括本发明的德罗格韦钠盐的晶型A或晶型D。
晶型B具有以下的有益性质：
①晶型B在室温下水中溶解度为2.1mg/mL，较已知的德罗格韦钠盐一水合物的溶解度(其在室温下水中溶解度为1.7mg/mL)高。
②晶型B在80℃-90％RH-6000lx的高温高湿光照条件下贮存10天后，其纯度的下降和最大单杂含量的增长明显低于已知的德罗格韦钠盐晶型I的数据，说明其稳定性较已知的德罗格韦钠盐晶型I好。
③晶型B在20％-80％相对湿度范围内的重量变化仅为约0.5％，相对于已知的德罗格韦钠盐一水合物晶型(其在20％-80％相对湿度范围内的重量变化为约4.3％)、已知的德罗格韦钠盐晶型I(其在20％-80％相对湿度范围内的重量变化为约1.1％)更不易吸湿。
④晶型B为杆状颗粒，比已知的德罗格韦钠盐一水合物的颗粒大。
晶型B的上述性质表明：与已知的德罗格韦钠盐晶型I或已知的德罗格韦钠盐一水合物相比，本发明晶型B具有溶解度高、贮存稳定性好、不易吸湿、颗粒形貌好的优点。其制剂可具有更高的溶出度和更好的生物利用度；颗粒流动性 好，便于制剂生产中的准确称量和倾倒，提高批次重现性；制剂的稳定性好，可适应更宽松的制造、贮存和运输的环境条件，更好地对抗由于环境温度、湿度、光照等因素可能产生的药物活性成分含量不均匀、纯度下降等问题，降低由此带来的疗效下降风险和安全风险。
根据本发明的目的，本发明提供德罗格韦钠盐的正丁醇溶剂化物晶型C(在本发明中简称为“晶型C”)。
所述晶型C为德罗格韦钠盐的正丁醇溶剂化物，且每摩尔晶型C含有约1摩尔正丁醇，其结构式如下所示：
Figure PCTCN2015074293-appb-000006
使用Cu-Kα辐射，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.2±0.2°、7.9±0.2°、12.5±0.2°、18.7±0.2°、21.3±0.2°和23.8±0.2°。
优选地，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和23.8±0.2°。
更优选地，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
Figure PCTCN2015074293-appb-000007
非限制性地，所述晶型C的一个典型实例具有如图22所示的X-射线粉末衍射图。
所述晶型C的傅里叶红外光谱在波数为3277、2956、2930、2873、1648、1624、1526、1506、1428、1283、1251、1087、981、839和743cm-1处具有特征峰。
所述晶型C的热重分析(TGA)图谱显示：样品150℃之前有15.17％的失重，约合含一分子正丁醇，分解温度为367℃。
所述晶型C的差式扫描量热(DSC)图显示：其在338℃开始熔融分解。
所述晶型C的制备方法，包括以下步骤：将德罗格韦钠盐在正丁醇中形成混悬液，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型C。
优选地，所述析晶的温度为10～60℃，更优选为30～50℃。
优选地，所述析晶的时间为12～48小时，更优选为12～24小时。
优选地，所述悬浊液中德罗格韦钠盐的用量为析晶温度下其在正丁醇中溶解度的2～10倍，更优选为2～5倍。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
上述晶型C的制备方法采用了晶浆的结晶方式，是将样品的过饱和溶液(有不溶解固体存在)在溶剂中搅拌，得到所需晶体。
上述晶型C的制备方法中，所述德罗格韦钠盐可以包括已知的德罗格韦钠盐的各种晶型或无定型物，例如包括但不限于根据专利文献WO2010068253A1实施例1l描述方法制备的已知的德罗格韦钠盐晶型I或根据专利文献WO2013038407A1实施例1的3.1方法I制备的已知的德罗格韦钠盐的无定型物；所述德罗格韦钠盐还可以包括本发明的德罗格韦钠盐的晶型A或晶型D。
晶型C具有以下的有益性质：
①晶型C在室温下水中溶解度为4.6mg/mL，较已知的德罗格韦钠盐晶型I的溶解度(其在室温下水中溶解度为2.1mg/mL)高，也较已知的德罗格韦钠盐一水合物的溶解度(其在室温下水中溶解度为1.7mg/mL)高。
②晶型C在室温、相对湿度10％～90％RH的干燥器中放置4个月，晶型不变。
晶型C的上述性质表明：与已知的德罗格韦钠盐晶型I和已知的德罗格韦钠盐一水合物相比，本发明的晶型C具有溶解度高、贮存稳定性好的优点。制剂可具有更高的溶出度和更好的生物利用度，并适应更宽松的制造、贮存和运输的环境条件，更好地对抗由于时间、湿度等因素可能产生的药物活性成分含量不均匀、纯度下降等问题，降低由此带来的疗效下降风险和安全风险。
根据本发明的目的，本发明提供德罗格韦钠盐的晶型D(在本发明中简称为“晶型D”)。
所述晶型D为德罗格韦钠盐的无水物，其结构式如下所示：
Figure PCTCN2015074293-appb-000008
使用Cu-Kα辐射，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、8.2±0.2°、13.0±0.2°、15.7±0.2°、18.5±0.2°和19.5±0.2°。
优选地，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和27.8±0.2°。
更优选地，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
Figure PCTCN2015074293-appb-000009
非限制性地，所述晶型D的一个典型实例具有如图27所示的X-射线粉末衍射图。
所述晶型D的傅里叶红外光谱在波数为2922、1636、1621、1531、1504、1425、1317、1280、1254、1198、1110、964、858和744cm-1处具有特征峰。
所述晶型D的热重分析(TGA)图谱显示：样品分解温度约为349℃。
所述晶型D的差式扫描量热(DSC)图显示：其在345℃开始熔融分解。
所述晶型D的制备方法，采用以下制备方法中的任意一种：
(1)将德罗格韦钠盐的正丁醇溶剂化物晶型C以5～20℃/分钟的升温速率从室温升温至脱溶剂温度150℃，在150℃下保持15～35分钟至完全脱去溶剂，然后以5～20℃/分钟的冷却速率冷却至室温，得到所述晶型D。
优选地，所述保持的时间为20～35分钟；更优选为20～30分钟。
优选地，所述升温速率为5～10℃/分钟。
优选地，所述冷却速率为10～20℃/分钟。
(2)将德罗格韦钠盐的正丁醇溶剂化物晶型C在130～150℃的环境中放置25～40分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型D。
优选地，所述环境的温度为140～150℃。
优选地，所述放置的时间为25～35分钟。
上述晶型D的制备方法采用了高温脱溶剂的结晶方式。
晶型D具有以下的有益性质：
①晶型D在室温下水中溶解度为4.2mg/mL，较已知的德罗格韦钠盐晶型I的溶解度(其在室温下水中溶解度为2.1mg/mL)高，也较已知的德罗格韦钠盐一水合物的溶解度(其在室温下水中溶解度为1.7mg/mL)高。
②晶型D在80℃-90％RH-6000lx的高温高湿光照条件下贮存10天后，其纯度的下降和最大单杂含量的增长明显低于已知的德罗格韦钠盐晶型I的数据，说明其稳定性较已知的德罗格韦钠盐晶型I好。
③晶型D在20％-80％相对湿度范围内重量变化仅为约0.1％，相对于已知的德罗格韦钠盐晶型I(其在20％-80％相对湿度范围内重量变化为约1.1％)及已知的德罗格韦钠盐一水合物(其在20％-80％相对湿度范围内重量变化为约4.3％)更不易吸湿。
④晶型D在室温、相对湿度10％～90％RH的干燥器中放置4个月，晶型不变。
晶型D的上述性质表明：与已知的德罗格韦钠盐晶型I和已知的德罗格韦钠盐一水合物相比，本发明的晶型D具有溶解度高、不易吸湿、贮存稳定性好的优点。能够满足固体制剂的使用要求，可加工性好，批次重现性好，制剂具有更高的溶出度和更好的生物利用度，并适应更宽松的制造、贮存和运输的环境条件，更好地对抗由于时间、湿度等因素可能产生的药物活性成分含量不均匀、纯度下降等问题，降低由此带来的疗效下降风险和安全风险。
根据本发明的目的，本发明提供德罗格韦钠盐的三氟乙醇溶剂化物晶型E(在本发明中简称为“晶型E”)。
所述晶型E为德罗格韦钠盐的三氟乙醇溶剂化物，且每摩尔晶型E含有约1摩尔的三氟乙醇，其结构式如下所示：
Figure PCTCN2015074293-appb-000010
使用Cu-Kα辐射，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、6.9±0.2°、11.2±0.2°、11.7±0.2°、19.2±0.2°和20.9±0.2°。
优选地，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和27.9±0.2°。
更优选地，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
Figure PCTCN2015074293-appb-000011
非限制性地，所述晶型E的一个典型实例具有如33所示的X-射线粉末衍射图。
所述晶型E的傅里叶红外光谱在波数为3419、3076、1641、1536、1503、1424、1321、1282、1258、1069、1023、963、763和722cm-1处具有特征峰。
所述晶型E的热重分析(TGA)图谱显示：样品150℃前有15.1％的失重，约合含一分子三氟乙醇，为三氟乙醇溶剂化物；分解温度为367℃。
所述晶型E的差式扫描量热(DSC)图显示其在在337℃开始熔融分解。
所述晶型E的制备方法，采用以下制备方法中的任意一种：
(1)将德罗格韦钠盐在三氟乙醇或三氟乙醇与有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自C1～C4醇、C4～C5酯、乙腈或其混合物，再自然挥发析晶，得到所述晶型E。
所述C1～C4醇可以是甲醇、乙醇、正丙醇、异丙醇、正丁醇或仲丁醇；所述C4～C5酯可以是乙酸乙酯或乙酸异丙酯。
优选地，所述有机溶剂选自乙醇、乙酸乙酯或乙腈。
优选地，所述三氟乙醇与有机溶剂的体积比为1:1～4:1，更优选为1:1～2:1。
优选地，所述制备方法的操作温度为20～60℃，更优选为30～50℃。
优选地，所述析晶的时间为1～5天，更优选为1～3天。
优选地，所述德罗格韦钠盐溶液的浓度为德罗格韦钠盐在三氟乙醇或所述混合溶剂中溶解度的0.2～1倍，优选为0.5～1倍，更优选为0.8～1倍。
上述晶型E的制备方法(1)采用了自然挥发析晶的结晶方式。具体操作是：将样品的澄清溶液放在敞口玻璃小瓶中，敞口或加盖打孔，自然挥发去除溶剂，获得晶体。
(2)向德罗格韦钠盐的三氟乙醇溶液中添加抗溶剂，其中所述抗溶剂选自C1～C4醇、C4～C5酯、异丙醚、乙腈、甲苯或其混合物，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型E。
所述C1～C4醇可以是甲醇、乙醇、正丙醇、异丙醇、正丁醇或仲丁醇；所述C4～C5酯可以是乙酸乙酯或乙酸异丙酯。
优选地，所述抗溶剂选自乙醇、乙酸乙酯或乙腈。
优选地，所述抗溶剂的体积为三氟乙醇体积的5～20倍，更优选为10～15倍。
优选地，所述析晶的温度为10～60℃，更优选为室温。
优选地，所述析晶的时间为1～24小时，更优选为1～5小时。
优选地，所述德罗格韦钠盐溶液的浓度为析晶温度下德罗格韦钠盐在三氟乙醇中溶解度的0.2～1倍，更优选为0.5～1倍。
优选地，所述干燥的温度为5～30℃，更优选为20～30℃。
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
上述晶型E的制备方法(2)采用了抗溶剂重结晶的结晶方式，是将样品溶解于良溶剂中，再添加适量抗溶剂，利用样品在不同溶剂中的溶解度差异析出晶体。
上述晶型E的制备方法中，所述德罗格韦钠盐可以包括已知的德罗格韦钠盐的各种晶型或无定型物，例如包括但不限于根据专利文献WO2010068253A1实施例1l描述方法制备的已知的德罗格韦钠盐晶型I或根据专利文献 WO2013038407A1实施例1的3.1方法I制备的已知的德罗格韦钠盐的无定型物；所述德罗格韦钠盐还可以包括本发明的德罗格韦钠盐的晶型A或晶型D。
晶型E具有以下的有益性质：
①晶型E在室温下水中溶解度为3.7mg/mL，较已知的德罗格韦钠盐晶型I的溶解度(其在室温下水中溶解度为2.1mg/mL)高，也较已知的德罗格韦钠盐一水合物的溶解度(其在室温下水中溶解度为1.7mg/mL)高，说明本发明晶型E具有更高的溶解度。
②晶型E在室温、相对湿度10％～90％RH的干燥器中放置4个月，晶型不变。
晶型E的上述性质表明：与已知的德罗格韦钠盐晶型I和已知的德罗格韦钠盐一水合物相比，本发明的晶型D具有溶解度高、贮存稳定性好的优点。制剂具有更高的溶出度和更好的生物利用度，并适应更宽松的制造、贮存和运输的环境条件，更好地对抗由于时间、湿度等因素可能产生的药物活性成分含量不均匀、纯度下降等问题，降低由此带来的疗效下降风险和安全风险。
本发明上述罗格韦钠盐的晶型A、晶型B、晶型C、晶型D或晶型E的制备方法中：
所述“室温”指约10～30℃的温度。
所述“搅拌”，可以采用本领域的常规方法完成，搅拌方式例如磁力搅拌、机械搅拌等，搅拌速度为50～1800转/分，优选为300～900转/分。
所述“分离”，可以采用本领域的常规技术完成，例如过滤或离心。所述过滤一般是在室温条件下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。所述离心的具体操作为：将欲分离的样品置于离心管中，以6000转/分的速率进行离心，直至固体全部沉至离心管底部。经所述“分离”得到的晶体可以进一步洗涤，洗涤所用的溶剂优选与晶体制备方法中所用的溶剂相同，洗涤溶剂的用量一般为晶体制备方法中所用的溶剂体积的0.3～1倍。
所述“无水物”是指样品经TGA检测含有不多于1.5％(重量比)或不多于1.0％(重量比)的水。
本发明通过提供新型的德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D和晶型E解决了现有技术晶型存在的问题，所述新晶型与已知晶型相比具有至少一种或多种有益的性质，例如：更高的溶解度、溶出速度、不易发生多晶型转化和/或脱水、热学和机械稳定性好、低吸湿性、更好的流动性、可压缩性和表观密度、储存稳定性好、低残留溶剂等。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何 具有与本发明图谱的特征峰相同或相似的晶型均属于本发明的范畴之内。
本发明所述“晶体”或“晶型”是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时，指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
此外，本发明还提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D、晶型E或者根据本发明制备方法得到的本发明的德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D、晶型E，以及至少一种药学上可接受的载体或助剂。所述药物组合物还可以包含德罗格韦钠盐的其它可药用的晶型或无定型物或德罗格韦的其它可药用盐的晶型或其无定型物。任选地，所述药物组合物包含一种或多种其它的药物活性成分，包括但不限于其他的抗病毒药物，例如具有不同作用机制的抗HIV药物如逆转录酶抑制剂和/或蛋白酶抑制剂。
所述药物组合物可以制成适当的药物制剂形式，可通过口服或胃肠外给药。适于口服给药的药物制剂，固体口服剂型例如包括片剂、颗粒剂、散剂、丸剂、粉末、胶囊剂等，液体口服剂型例如包括溶液剂、糖浆剂、混悬剂、乳液剂等，所述混悬剂中本发明的德罗格韦钠盐的晶型保持为固体形式。适于肠胃外给药的药物制剂，例如包括静脉滴注制剂，肌肉或皮下注射剂，经直肠给药的栓剂，经阴道给药的喷剂、糊剂，经鼻内给药的吸入制剂或局部给药的透皮贴剂形式。配方可适于活性成分的快速释放、延迟释放或调节释放。
固体口服剂型中，所述药物组合物中药学上可接受的载体或助剂包括但不限于：稀释剂，例如淀粉、改性淀粉、乳糖、粉状纤维素、微晶纤维素、无水磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、共聚维酮等；崩解剂，例如淀粉、羧甲基淀粉钠、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。其他可用的药学上可接受的载体包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。液体口服剂型中，所述药物组合物中药学上可接受的载体或助剂包括水性、油性或醇类溶液的溶剂例如无菌水、生理盐水溶液、葡萄糖溶液、甘露糖醇溶液、植物油、鱼肝油、乙醇、丙醇、甘油等。此外，还可以使用聚乙二醇、聚丙二醇等载体。适合胃肠外给药的情况下，水或非水的无菌溶液注射剂可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质，水或非水的无菌混悬剂可以含有悬浮剂和增稠剂。每一种载体或助剂必须是可接受的，能与配方中的其他成分兼容并且对于病患无害。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组 合物时，将本发明德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D或晶型E与一种或多种药学上可接受的载体或助剂相混合，任选地，与一种或多种其他的药物活性成分相混合。固体制剂可以通过混合、制粒等工艺来制备。液体制剂可以通过溶解、分散、乳化等工艺来制备。
本发明德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D或晶型E对病毒的整合酶具有显著的抑制作用，作为逆转录病毒(包括HIV-1、HIV-2、HTLV-1、SIV-1、FIV-1)的整合酶抑制剂，特别是用于制备治疗和/或预防HIV感染的药物。
此外，本发明提供一种治疗和/或预防HIV-1感染的方法，所述方法包括给与需要的患者治疗和/或预防有效量的选自本发明的德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D、晶型E或者含有本发明德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D或晶型E的前述药物组合物。根据给药方法、患者年龄、体重和病情的不同而使用不同的剂量。通常在口服给药的情况下，每个成人每日给予约0.1mg～1000mg；在胃肠外给药的情况下，每个成人每日给予约0.05mg～500mg。
附图说明
图1为制备例1制备的已知的德罗格韦钠盐晶型I的XRPD图。
图2为制备例1制备的已知的罗格韦钠盐晶型I的PLM图。
图3为制备例1制备的已知的德罗格韦钠盐晶型I的等温吸附曲线图。
图4为制备例1制备的已知的德罗格韦钠盐晶型I的IR图。
图5为制备例2制备的已知的德罗格韦钠盐无定型物的XRPD图。
图6为制备例3制备的已知的德罗格韦钠盐一水合物的XRPD图。
图7为制备例3制备的已知的德罗格韦钠盐一水合物的PLM图。
图8为制备例3制备的已知的德罗格韦钠盐一水合物的等温吸附曲线图。
图9为制备例3制备的已知的德罗格韦钠盐一水合物的IR图。
图10为本发明德罗格韦钠盐的晶型A的XRPD图。
图11为本发明德罗格韦钠盐的晶型A的PLM图。
图12为本发明德罗格韦钠盐的晶型A的DSC图。
图13为本发明德罗格韦钠盐的晶型A的TGA图。
图14为本发明德罗格韦钠盐的晶型A的等温吸附曲线图。
图15为本发明德罗格韦钠盐的晶型A的IR图。
图16为本发明德罗格韦钠盐的晶型B的XRPD图。
图17为本发明德罗格韦钠盐的晶型B的PLM图。
图18为本发明德罗格韦钠盐的晶型B的DSC图。
图19为本发明德罗格韦钠盐的晶型B的TGA图。
图20为本发明德罗格韦钠盐的晶型B的等温吸附曲线图。
图21为本发明德罗格韦钠盐的晶型B的IR图。
图22为本发明德罗格韦钠盐的晶型C的XRPD图。
图23为本发明德罗格韦钠盐的晶型C的PLM图。
图24为本发明德罗格韦钠盐的晶型C的DSC图。
图25为本发明德罗格韦钠盐的晶型C的TGA图。
图26为本发明德罗格韦钠盐的晶型C的IR图。
图27为本发明德罗格韦钠盐的晶型D的XRPD图。
图28为本发明德罗格韦钠盐的晶型D的PLM图。
图29为本发明德罗格韦钠盐的晶型D的DSC图。
图30为本发明德罗格韦钠盐的晶型D的TGA图。
图31为本发明德罗格韦钠盐的晶型D的等温吸附曲线图。
图32为本发明德罗格韦钠盐的晶型D的IR图。
图33为本发明德罗格韦钠盐的晶型E的XRPD图。
图34为本发明德罗格韦钠盐的晶型E的PLM图。
图35为本发明德罗格韦钠盐的晶型E的DSC图。
图36为本发明德罗格韦钠盐的晶型E的TGA图。
图37为本发明德罗格韦钠盐的晶型E的IR图。
具体实施方案
本发明进一步参考以下实施例，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
采集数据所用的仪器及方法：
X-射线粉末衍射(XPRD)：所使用的仪器为Bruker D8Advance diffractometer，采用铜靶波长为1.54nm的Ka X-射线，在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用仪器自带的标准品(一般为刚玉)校准。样品在室温条件下测试，把需要检测的样品放在无反射板上。详细检测条件如下，角度范围：3–40°2θ，步长：0.02°2θ，速度：0.2秒/步。
偏振光显微镜(PLM)图采自于XP-500E偏振光显微镜(上海长方光学仪器有限公司)。取少量粉末样品置于载玻片上，滴加少量矿物油以更好地分散粉末样品，盖上盖玻片，然后将样品放置在XP-500E偏振光显微镜的载物台上，选择合适的放大倍数观测样品的形貌并拍照。
差热分析(DSC)数据采自于TA Instruments Q200MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10mg的样品放置于铝盘内，以10℃/分钟的升温速度在40mL/分钟干燥氮气的保护下将样品从0℃升至375℃或400℃。
热重分析(TGA)数据采自于TA Instruments Q500TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/分钟的升温速度在40mL/分钟干燥氮气的保护下将样品从室温升至400℃或450℃。
等温吸附曲线：数据采自于TA Instruments Q5000TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10mg的样品放置于白金坩埚内，TA软件记录样品在相对湿度从0％到80％到0％变化过程中 的重量变化。根据样品的具体情况，也会对样品采用不同的吸附和脱吸附步骤。
红外光谱分析(IR)数据采自于BrukerTensor 27，仪器控制软件和数据分析软件都是OPUS，通常采用ATR设备，在600-4000cm-1范围内采集红外吸收光谱，样品和空白背景的扫描时间均为16秒，仪器分辨率为4cm-1。
高效液相分析(HPLC)数据采自于Agilent 1260，仪器控制软件是Agilent化学工作站B.04版online，分析软件是Agilent化学工作站B.04版offline。采用C18色谱柱，250mm*4.6mm，柱温35℃，波长254nm，流速0.7mL/分钟，进样量20μL，运行时间30分钟。流动相A为含0.01mol/L磷酸二氢钾，流动相B为乙腈，流动相A:流动相B＝55:45。
实施例中所用的各种试剂如无特别说明均为商购获得。
实施例中的温度如无特别说明均为室温。
实施例中，混合溶剂中组分的比例如无特别说明均为体积比。
实施例中的超声操作可以促进样品溶解，设备为超声波清洗器，40kHz功率下进行5分钟。
制备例1制备已知的德罗格韦钠盐晶型I
已知的德罗格韦钠盐晶型I可根据专利文献WO2010/068253A1实施例1l描述的方法制备得到。
具体制备方法为：通过加热将12.0g德罗格韦溶解在36mL乙醇中，在80℃下将14.5mL 2N的NaOH水溶液加入到该溶液中，将该溶液逐渐冷却至室温，过滤，用50mL乙醇洗涤并50℃干燥，得到德罗格韦钠盐。
XRPD图见图1，显示与专利文献WO2010/068253A1公开的德罗格韦钠盐的晶型I一致。
PLM图见图2，显示为较小、棒状颗粒。
等温吸附曲线图见图3，显示：20％-80％相对湿度范围内重量变化为1.1％。
IR图见图4，显示与专利文献WO2010/068253A1公开的德罗格韦钠盐的晶型I一致。
制备例2制备已知的德罗格韦钠盐无定型物
已知的德罗格韦钠盐无定型物可参考专利文献WO2013/038407A1实施例1的3.1方法I制备得到。
具体为：称取40mg制备例1制备的德罗格韦钠盐晶型I，用球磨机以200转/分钟的速度球磨200分钟，即得到德罗格韦钠盐无定型物。
XRPD图见图5，显示无特征峰，为无定型物。
制备例3制备已知的德罗格韦钠盐一水合物
已知的德罗格韦钠盐一水合物可根据专利文献WO2010/068253A1实施例1m描述的方法制备得到。
具体制备方法为：30℃下将10g德罗格韦钠盐溶解在200mL四氢呋喃-水(4:1)溶液中，再加入12mL的2N NaOH水溶液。将混合物在室温下搅拌2小时，过滤，滤饼用100mL四氢呋喃-水(4:1)溶液和100mL四氢呋喃洗涤，85℃干燥，得到德罗格韦钠盐一水合物。
XRPD图见图6，显示与专利文献WO2010/068253A1公开的德罗格韦钠盐的一水合物晶型一致。
PLM图见图7，显示为小颗粒。
等温吸附曲线图见图8，显示：20％-80％相对湿度范围内重量变化为4.3％。
IR图见图9，显示与专利文献WO2010/068253A1公开的德罗格韦钠盐的一水合物晶型一致。
实施例1
称取40mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL水:乙腈(4:1)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐晶型I的用量为析晶温度下其在所述混合溶剂中溶解度的2倍)，将此混悬液在60℃搅拌5天，过滤，滤饼用2.0mL水:乙腈(4:1)的混合溶剂洗涤，40℃真空干燥10小时，得到38.4mg德罗格韦钠盐晶型A。
XRPD图见图10。
PLM图见图11，显示：为较小、不规则状颗粒。
DSC图见图12。
TGA图见图13，显示：在150℃之前失重1.0％，为无水物。
等温吸附曲线图见图14，显示：20％-80％相对湿度范围内重量变化为1.0％。
IR图见图15。
实施例2
称取100mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL水:1,4-二氧六环(5:1)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐晶型I的用量为析晶温度下其在所述混合溶剂中溶解度的5倍)，将此混悬液在50℃搅拌6天，过滤，滤饼用1.5mL水:1,4-二氧六环(5:1)的混合溶剂洗涤，30℃干燥15小时，得到92.1mg德罗格韦钠盐晶型A。
实施例3
称取90mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL水:丙酮(4.5:1)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐无定型物的用量为析晶温度下其在所述混合溶剂中溶解度的4.5倍)，将此混悬液在40℃搅拌8天，过滤，用3.5mL水:丙酮(4.5:1)的混合溶剂洗涤，10℃干燥24小时，得到80.9mg德罗格韦钠盐晶型A。
实施例4
称取100mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL水:丁酮(3:1)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐无定型物的用量为析晶温度下其在所述混合溶剂中溶解度的10倍)，将此混悬液在10℃搅拌14天，过滤，滤饼用5.0mL水:丁酮(3:1)的混合溶剂洗涤，60℃干燥48小时，得到17.4mg德罗格韦钠盐晶型A。
实施例2～4制备的样品具有与实施例1样品相同或相似的XRPD图、IR图、PLM图、DSC图、TGA图和等温吸附曲线图(未示出)。说明实施例2～4样品与实施例1样品是相同的物质。
实施例5
称取60mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL水:四氢呋喃(1:4)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐晶型I的用量为析晶温度下其在所述混合溶剂中溶解度的2倍)，将此混悬液在60℃搅拌1天，过滤，滤饼用2.0mL水:四氢呋喃(1:4)的混合溶剂洗涤，10℃真空干燥24小时，得到58.7mg德罗格韦钠盐的晶型B。
XRPD图见图16。
PLM图见图17，显示：为杆状颗粒。
DSC图见图18。
TGA图见图19，显示：在150℃之前失重6.2％(含表面水2.0％)，约合含一分子水。
等温吸附曲线图见图20，显示：20％-80％相对湿度范围内重量变化为0.5％，说明不易吸湿。
IR图见图21。
实施例6
称取150mg本发明的德罗格韦钠盐的晶型A，添加5.0mL水:1,4-二氧六环(1:5)的混合溶剂形成混悬液(该混悬液中本发明的德罗格韦钠盐晶型A的用量为析晶温度下其在所述混合溶剂中溶解度的3倍)，将此混悬液在50℃搅拌2天，过滤，滤饼用4.0mL水:1,4-二氧六环(1:5)的混合溶剂洗涤，15℃干燥18小时，得到150.0mg德罗格韦钠盐的晶型B。
实施例7
称取90mg本发明的德罗格韦钠盐的晶型D，添加5.0mL水:正丙醇(1:4.5)的混合溶剂形成混悬液(该混悬液中本发明的德罗格韦钠盐晶型D的用量为析晶温度下其在所述混合溶剂中溶解度的4倍)，将此混悬液在30℃搅拌3天，过滤，滤饼用1.5mL水:正丙醇(1:4.5)的混合溶剂洗涤，16℃干燥14小时，得到86.0mg德罗格韦钠盐的晶型B。
实施例8
称取30mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL水:二甲亚砜(1:3)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐晶型I的用量为析晶温度下其在所述混合溶剂中溶解度的5倍)，将此混悬液在20℃搅拌4天，过滤，滤饼用3.0mL水:二甲亚砜(1:3)的混合溶剂洗涤，18℃干燥12小时，得到28.0mg德罗格韦钠盐的晶型B。
实施例9
称取300mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL水:正丁醇(1:4.2)的混合溶剂形成混悬液(该混悬液中已知的德罗格韦钠盐无定型物的用量为析晶温度下其在所述混合溶剂中溶解度的10倍)，将此混悬液在10℃搅拌5天，过滤，滤饼用1.5mL水:正丁醇(1:4.2)的混合溶剂洗涤，20℃干燥10小时，得到270.8mg德罗格韦钠盐的晶型B。
实施例6～9制备的样品具有与实施例5样品相同或相似的XRPD图、IR图、 PLM图、DSC图、TGA图和等温吸附曲线图(未示出)。说明实施例6～9样品与实施例5样品是相同的物质。
实施例10
称取50mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL正丁醇形成混悬液(该混悬液中已知德罗格韦钠盐晶型I的用量为析晶温度下其在正丁醇中溶解度的2倍)，将此混悬液在50℃搅拌12小时，过滤，滤饼用1.5mL正丁醇洗涤，40℃真空干燥10小时，得到54.7mg德罗格韦钠盐的晶型C。
XRPD图见图22。
PLM图见图23，显示为小颗粒。
DSC图见图24。
TGA图见图25，显示：在150℃之前失重15.2％，约合含一分子正丁醇。
IR图见图26。
实施例11
称取75mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL正丁醇形成混悬液(该混悬液中已知的德罗格韦钠盐晶型I的用量为析晶温度下其在正丁醇中溶解度的3倍)，将此混悬液在40℃搅拌18小时，过滤，滤饼用3.0mL正丁醇洗涤，35℃干燥13小时，得到80.3mg德罗格韦钠盐的晶型C。
实施例12
称取125mg本发明的德罗格韦钠盐的晶型A，添加5.0mL正丁醇形成混悬液(该混悬液中本发明的德罗格韦钠盐的晶型A的用量为析晶温度下其在正丁醇中溶解度的5倍)，30℃搅拌24小时，过滤，滤饼用3.0mL正丁醇洗涤，10℃干燥48小时，得到129.5mg德罗格韦钠盐的晶型C。
实施例13
称取25mg本发明的德罗格韦钠盐的晶型D，添加5.0mL正丁醇形成混悬液(该混悬液中本发明的德罗格韦钠盐晶型D的用量为析晶温度下其在正丁醇中溶解度的2倍)，将此混悬液在60℃搅拌13小时，过滤，滤饼用3.0mL正丁醇洗涤，18℃干燥16小时，得到25.3mg德罗格韦钠盐的晶型C。
实施例14
称取250mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL正丁醇溶剂形成混悬液(该混悬液中已知德罗格韦钠盐无定型物的用量为析晶温度下其在正丁醇中溶解度的10倍)，将此混悬液在10℃搅拌48小时，过滤，滤饼用3.0mL正丁醇洗涤，60℃干燥28小时，得到244.7mg德罗格韦钠盐的晶型C。
实施例11～14制备的样品具有与实施例10样品相同或相似的XRPD图、IR图、PLM图、DSC图和TGA图(未示出)。说明实施例11～14样品与实施例10样品是相同的物质。
实施例15
将实施例10制备的20mg德罗格韦钠盐的晶型C以10℃/分钟从室温升温至150℃，在150℃下保持30分钟至完全脱去溶剂,然后以10℃/分钟冷却至室温，即得到16.9mg德罗格韦钠盐的晶型D。
XRPD图见图27。
PLM图见图28，显示：为小颗粒。
DSC图见图29。
TGA图见图30。
等温吸附曲线图见图31，显示：20％～80％相对湿度范围内重量变化为0.06％。
IR图见图32。
实施例16
将实施例10制备的30mg德罗格韦钠盐的晶型C以8℃/分钟升温至150℃，在150℃保持25分钟至完全脱去溶剂,然后以15℃/分钟冷却至室温，即得到25.4mg德罗格韦钠盐的晶型D。
实施例17
将实施例10制备的50mg德罗格韦钠盐的晶型C以5℃/分钟升温至150℃，在150℃保持20分钟至完全脱去溶剂,然后以20℃/分钟冷却至室温，即得到42.4mg德罗格韦钠盐的晶型D。
实施例18
将实施例10制备的28mg德罗格韦钠盐的晶型C以15℃/分钟升温至150℃，在150℃保持33分钟至完全脱去溶剂,然后以8℃/分钟冷却至室温，即得到23.8mg德罗格韦钠盐的晶型D。
实施例19
将实施例10制备的26mg德罗格韦钠盐的晶型C以20℃/分钟升温至150℃，在150℃保持35分钟至完全脱去溶剂,然后以5℃/分钟冷却至室温，即得到22.1mg德罗格韦钠盐的晶型D。
实施例20
将实施例10制备的30mg德罗格韦钠盐的晶型C放入140℃烘箱中，保持35分钟至完全脱去溶剂，取出室温放置，即得到25.4mg德罗格韦钠盐的晶型D。
实施例21
将实施例10制备的50mg德罗格韦钠盐的晶型C放入150℃烘箱中，在150℃保持25分钟至完全脱去溶剂，取出室温放置，即得到42.4mg德罗格韦钠盐的晶型D。
实施例22
将实施例10制备的45mg德罗格韦钠盐的晶型C放入145℃烘箱中，在145℃保持30分钟至完全脱去溶剂，取出室温放置，即得到38.2mg德罗格韦钠盐的晶型D。
实施例23
将实施例10制备的45mg德罗格韦钠盐的晶型C放入至130℃烘箱中，在130℃保持40分钟至完全脱去溶剂，取出室温放置，即得到38.2mg德罗格韦钠盐的晶型D。
实施例16～23制备的样品具有与实施例15样品相同或相似的XRPD图、IR图、PLM图、DSC图、TGA图和等温吸附曲线图(未示出)。说明实施例16～23 样品与实施例15样品是相同的物质。
实施例24
称取60mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0ml三氟乙醇，40℃超声使溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在三氟乙醇中溶解度的1倍)，然后自然挥发析晶2天，得到69.0mg德罗格韦钠盐的晶型E。
XRPD图见图33。
PLM图见图34，显示为杆状颗粒。
DSC图见图35。
TGA图见图36，显示：在150℃之前失重15.12％，约合含一分子三氟乙醇。
IR图见图37。
实施例25
称取48mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0ml三氟乙醇：乙醇(1:1)的混合溶剂，30℃超声使溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在该混合溶剂中溶解度的0.8倍)，然后自然挥发析晶3天，得到55.2mg德罗格韦钠盐的晶型E。
实施例26
称取54mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0ml三氟乙醇：乙酸乙酯(2:1)的混合溶剂，50℃超声使溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在该混合溶剂中溶解度的0.9倍)，然后自然挥发析晶1天，得到62.1mg德罗格韦钠盐的晶型E。
实施例27
称取30mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇:乙腈(1.5:1)的混合溶剂，20℃超声使溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在该混合溶剂中溶解度的0.5倍)，然后自然挥发析晶5天，得到34.5mg德罗格韦钠盐的晶型E。
实施例28
称取12mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇:正丁醇(4:1)的混合溶剂，60℃超声使溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在该混合溶剂中溶解度的0.6倍)，然后自然挥发析晶4天，得到13.8mg德罗格韦钠盐的晶型E。
实施例29
称取48mg本发明的德罗格韦钠盐晶型D，添加5.0mL三氟乙醇:甲醇(1:1)的混合溶剂，45℃超声使溶清(该溶液的浓度为本发明的德罗格韦钠盐晶型D在该混合溶剂中溶解度的0.7倍)，然后自然挥发析晶4天，得到55.2mg德罗格韦钠盐的晶型E。
实施例30
称取18mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇:乙酸异丙酯(1.6:1)的混合溶剂，45℃超声使溶清(该的浓度为已知的德罗格 韦钠盐晶型I在该混合溶剂中溶解度的0.3倍)，然后自然挥发析晶5天，得到20.7mg德罗格韦钠盐的晶型E。
实施例31
称取60mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在三氟乙醇中溶解度的1倍)，然后往溶清液中加入50mL乙醇，室温搅拌1小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，30℃干燥10小时，得到66.3mg德罗格韦钠盐的晶型E。
实施例32
称取54mg本发明的德罗格韦钠盐晶型A，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为本发明的德罗格韦钠盐晶型A在三氟乙醇中溶解度的0.9倍)，然后往溶清液中加入60mL乙酸乙酯，室温搅拌2小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，25℃干燥18小时，得到58.4mg德罗格韦钠盐的晶型E。
实施例33
称取48mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为已知的德罗格韦钠盐无定型物在三氟乙醇中溶解度的0.8倍)，然后往溶清液中加入75mL乙腈，室温搅拌5小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，20℃干燥24小时，得到51.4mg德罗格韦钠盐的晶型E。
实施例34
称取30mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在三氟乙醇中溶解度的0.5倍)，然后往溶清液中加入25mL甲醇，50℃搅拌12小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，15℃干燥28小时，得到31.8mg德罗格韦钠盐的晶型E。
实施例35
称取12mg制备例1制备的已知的德罗格韦钠盐晶型I，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为已知的德罗格韦钠盐晶型I在三氟乙醇中溶解度的0.2倍)，然后往溶清液中加入100mL正丁醇，室温搅拌24小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，10℃干燥30小时，得到12.4mg德罗格韦钠盐的晶型E。
实施例36
称取16mg制备例1制备的本发明的德罗格韦钠盐晶型D，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为本发明的德罗格韦钠盐晶型D在三氟乙醇中溶解度的0.4倍)，然后往溶清液中加入40mL乙酸异丙酯，40℃搅拌20小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，5℃干燥48小时，得到16.4mg德罗格韦钠盐的晶型E。
实施例37
称取48mg本发明的德罗格韦钠盐晶型A，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为本发明的德罗格韦钠盐晶型A在三氟乙醇中溶解度的0.8倍)，然后往溶清液中加入75mL甲苯，室温搅拌13小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，5℃干燥48小时，得到48.1mg德罗格韦钠盐的晶型E。
实施例38
称取54mg制备例2制备的已知的德罗格韦钠盐无定型物，添加5.0mL三氟乙醇，超声溶清(该溶液的浓度为已知的德罗格韦钠盐无定型物在三氟乙醇中溶解度的0.9倍)，然后往溶清液中加入65mL异丙醚，60℃搅拌16小时析出固体，过滤，滤饼用3.0mL三氟乙醇洗涤，5℃干燥48小时，得到51.6mg德罗格韦钠盐的晶型E。
实施例25～38制备的样品具有与实施例24样品相同或相似的XRPD图、IR图、PLM图、DSC图和TGA图(未示出)。说明实施例25～38样品与实施例24样品是相同的物质。
实施例39
制备含本发明的德罗格韦钠盐晶型A的片剂。
片剂(每片含50mg德罗格韦游离碱)配方如下：
本发明的德罗格韦钠盐晶型A：52.6mg
甘露醇：187.0mg
聚维酮：15.0mg
羧甲基淀粉钠：12.4mg
微晶纤维素：30.0mg
硬脂酸镁：3.0mg
总计：300.0mg
片剂的制备步骤如下：
以一万片的规模，将本发明的德罗格韦钠盐晶型A与甘露醇采用等量递增方法混合均匀，再与微晶纤维素、羧甲基淀粉钠、聚维酮、硬脂酸镁混合均匀后，置于压片机中压片，调节片重，即得相应片剂。
实施例40-43
制备分别含本发明德罗格韦钠盐的晶型B、晶型C、晶型D和晶型E的片剂。
各片剂配方如下：将实施例39中德罗格韦钠盐的晶型A分别替换为本发明制备的德罗格韦钠盐的晶型B、晶型C、晶型D和晶型E，其中，所述晶型B、晶型C、晶型D和晶型E的配方中德罗格韦的摩尔用量与德罗格韦钠盐晶型A配方中的相同，各配方中的其他组分也与实施例39中的相同。
各片剂的制备步骤也同实施例39。
实施例44
对实施例39～43制备的片剂(素片)进行包衣。
包衣粉的配方如下(每片的用量)：
氧化铁黄：3.0mg
聚乙二醇8.0mg
滑石粉2.0mg
二氧化钛2.0mg
总计：15.0mg
包衣的操作步骤：将实施例39～43制备的片剂(素片)，通过高效包衣机用上述配方组分混合制备的包衣粉进行包衣即可。
测试例1
针对本发明德罗格韦钠盐的晶型A、已知的德罗格韦钠盐晶型I及已知的德罗格韦钠盐一水合物，进行稳定性竞争实验比较，结果见表1。
所述稳定性竞争实验的操作过程是：分别取等量(250mg)的本发明德罗格韦钠盐的晶型A、制备例1制备的已知的德罗格韦钠盐晶型I及制备例3制备的已知的德罗格韦钠盐一水合物，混合后置于3mL水中，形成混悬液，室温下搅拌7天后，进行XRPD表征。结果见表1。
表1稳定性竞争实验结果
Figure PCTCN2015074293-appb-000012
由表1结果可知：通过室温下、在水中晶浆的稳定性竞争实验，已知的德罗格韦钠盐晶型I及已知的德罗格韦钠盐一水合物均转变为本发明的德罗格韦钠盐晶型A，而本发明的德罗格韦钠盐晶型A保持晶型不变，说明本发明的德罗格韦钠盐晶型A比已知的德罗格韦钠盐晶型I及已知的德罗格韦钠盐一水合物更稳定，从而更适合固体制剂的湿法制粒工艺，在含水体系的湿法制粒过程中晶型稳定。
测试例2
分别取本发明制备的德罗格韦钠盐的晶型A、晶型B、晶型C、晶型D及晶型E，对比样为制备例1～3制备的已知的德罗格韦钠盐晶型I、德罗格韦钠盐无定型物及德罗格韦钠盐一水合物，进行室温下水中溶解度、吸湿性、熔点、分解温度和颗粒形貌的比较。结果见表2。
溶解度检测：取50mg样品于20ml玻璃瓶中，加入15ml去离子水，26℃搅拌1天，取样过滤并定容至5ml容量瓶中，用乙腈/水(1:1)定容，通过HPLC检测浓度。
分解温度检测：通过TGA检测获得。
熔点检测：通过DSC检测获得。
吸湿性检测：通过DVS检测20％-80％RH范围内的重量变化获得。
颗粒形貌检测：通过PLM检测获得。
表2不同晶型的德罗格韦钠盐的性能比较结果
Figure PCTCN2015074293-appb-000013
*注：德罗格韦钠盐无定型物在水中搅拌5分钟即转变为德罗格韦钠盐晶型I，因此两者的表观溶解度一致。
由表2的检测结果可以看出：本发明的德罗格韦钠盐的晶型A，较已知的德罗格韦钠盐一水合物，更不易吸湿；本发明的德罗格韦钠盐的晶型B与已知的德罗格韦钠盐一水合物比较，具有溶解度高、不易吸湿、颗粒形貌好等优势；本发明的德罗格韦钠盐的晶型C、晶型D、晶型E与已知的德罗格韦钠盐晶型I、德罗格韦钠盐无定型物及已知的德罗格韦钠盐一水合物比较，具有溶解度高的优势；本发明的德罗格韦钠盐的晶型D，较已知的德罗格韦钠盐晶型I和德罗格韦钠盐一水合物，更不易吸湿。
测试例3
分别取本发明制备的德罗格韦钠盐的晶型A、晶型B及晶型D，对比样为制备例1制备的已知的德罗格韦钠盐晶型I，进行高温高湿光照条件下放置10天的稳定性实验。高温条件为80℃，高湿条件为90％RH，光照条件为6000lx照度。检测样品在放置前后的HPLC纯度和最大单杂含量，结果见表3。
表3不同晶型的德罗格韦钠盐的稳定性比较结果
Figure PCTCN2015074293-appb-000014
由表3可知：在高温高湿光照10天的条件下，已知的德罗格韦钠盐晶型I纯度降低了2.8％，最大单杂含量增加了3.1％；而本发明的德罗格韦钠盐晶型A纯度降低了0.5％，最大单杂含量增加了0.1％，本发明的德罗格韦钠盐晶型B纯度降低了0.3％，最大单杂含量增加了0.05％，本发明的德罗格韦钠盐晶型D纯度降低了0.4％，最大单杂含量仅增加了0.02％。
因此，本发明的德罗格韦钠盐晶型A、晶型B及晶型D在高温高湿光照下的稳定性明显优于已知的德罗格韦钠盐晶型I。
本说明书中所引用的所有专利文献及非专利出版物，均通过引用以其全文并入本文中。
上述对本发明中涉及的发明的一般性描述和对其具体实施方式的描述不应理解为是对该发明技术方案构成的限制。本领域所属技术人员根据本发明的公开，可以在不违背所涉及的发明构成要素的前提下，对上述一般性描述或/和具体实施方式(包括实施例)中的公开技术特征进行增加、减少或组合，形成属于所述发明的其它的技术方案。本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (28)

  1. 结构式如下所示的德罗格韦钠盐的晶型A，
    Figure PCTCN2015074293-appb-100001
    其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、9.0±0.2°、9.3±0.2°、13.9±0.2°、19.2±0.2°和21.8±0.2°。
  2. 根据权利要求1所述的德罗格韦钠盐的晶型A，其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和28.7±0.2°。
  3. 根据权利要求2所述的德罗格韦钠盐的晶型A，其特征在于，所述晶型A以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
    Figure PCTCN2015074293-appb-100002
  4. 根据权利要求1～3中任一项所述德罗格韦钠盐的晶型A，其特征在于，所述晶型A的傅里叶红外光谱在波数为2942、1641、1537、1503、1424、1321、1278、1258、1094、1069、964、854、763和722cm-1处具有特征峰。
  5. 一种权利要求1～4中任一项所述的德罗格韦钠盐的晶型A的制备方法，包括以下步骤：将已知的德罗格韦钠盐在水与有机溶剂的混合溶剂中形成混悬液，其中所述有机溶剂选自乙腈、1,4-二氧六环、丙酮、丁酮或其混合物，水与有机溶剂的体积比为3:1～5:1，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型A；
    优选地，所述有机溶剂为乙腈或1,4-二氧六环；
    优选地，所述水与有机溶剂的体积比为4:1～5:1；
    优选地，所述析晶的温度为10～60℃，更优选为40～60℃；
    优选地，所述析晶的时间为5～14天，更优选为5～8天；
    优选地，所述混悬液中已知的德罗格韦钠盐的用量为析晶温度下其在所述混合溶剂中溶解度的2～10倍，更优选为2～5倍；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
  6. 结构式如下所示的德罗格韦钠盐的一水合物晶型B，
    Figure PCTCN2015074293-appb-100003
    其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：7.9±0.2°、9.0±0.2°、11.1±0.2°、15.1±0.2°、15.9±0.2°和22.4±0.2°。
  7. 根据权利要求6所述的德罗格韦钠盐的一水合物晶型B，其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和26.3±0.2°。
  8. 根据权利要求7所述的德罗格韦钠盐的一水合物晶型B，其特征在于，所述晶型B以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
    Figure PCTCN2015074293-appb-100004
  9. 根据权利要求6～8中任一项所述德罗格韦钠盐的一水合物晶型B，其特征在于，所述晶型B的傅里叶红外光谱在波数为2968、1645、1537、1502、1424、1320、1278、1258、1095、1068、964、875、846、762和731cm-1处具有特征峰。
  10. 一种权利要求6～9中任一项所述的德罗格韦钠盐一水合物晶型B的制备方法，包括以下步骤：将德罗格韦钠盐在水与有机溶剂的混合溶剂中形成混悬液，其中所述有机溶剂选自二甲亚砜、四氢呋喃、1,4-二氧六环、C3～C4醇或其混合物，水与有机溶剂的体积比为1:3～1:5，搅拌析晶，将析出的晶体分离，在10～30℃下干燥10～48小时，得到所述晶型B；
    优选地，所述有机溶剂为四氢呋喃或1,4-二氧六环；
    优选地，所述水与有机溶剂的体积比为1:4～1:5；
    优选地，所述析晶的温度为10～60℃，更优选为30～50℃；
    优选地，所述析晶的时间为1～5天，更优选为1～3天；
    优选地，所述混悬液中德罗格韦钠盐的用量为析晶温度下其在所述混合溶剂中溶解度的2～10倍，更优选为2～5倍；
    优选地，所述干燥的温度为10～20℃；所述干燥的时间为10～24小时。
  11. 结构式如下所示的德罗格韦钠盐的正丁醇溶剂化物晶型C，
    Figure PCTCN2015074293-appb-100005
    其特征在于，使用Cu-Kα辐射，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.2±0.2°、7.9±0.2°、12.5±0.2°、18.7±0.2°、21.3±0.2°和23.8±0.2°。
  12. 根据权利要求11所述的德罗格韦钠盐的正丁醇溶剂化物晶型C，其特征在于，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和23.8±0.2°。
  13. 根据权利要求12所述的德罗格韦钠盐的正丁醇溶剂化物晶型C，其特征在于，所述晶型C以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
    Figure PCTCN2015074293-appb-100006
    Figure PCTCN2015074293-appb-100007
  14. 根据权利要求11～13中任一项所述德罗格韦钠盐的正丁醇溶剂化物晶型C，其特征在于，所述晶型C的傅里叶红外光谱在波数为3277、2956、2930、2873、1648、1624、1526、1506、1428、1283、1251、1087、981、839和743cm-1处具有特征峰。
  15. 一种权利要求11～14中任一项所述的德罗格韦钠盐的正丁醇溶剂化物晶型C的制备方法，包括以下步骤：将德罗格韦钠盐在正丁醇中形成混悬液，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型C；
    优选地，所述析晶的温度为10～60℃，更优选为30～50℃；
    优选地，所述析晶的时间为12～48小时，更优选为12～24小时；
    优选地，所述混悬液中德罗格韦钠盐的用量为析晶温度下其在正丁醇中溶解度的2～10倍，更优选为2～5倍；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
  16. 结构式如下所示的德罗格韦钠盐的晶型D，
    Figure PCTCN2015074293-appb-100008
    其特征在于，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、8.2±0.2°、13.0±0.2°、15.7±0.2°、18.5±0.2°和19.5±0.2°。
  17. 根据权利要求16所述的德罗格韦钠盐的晶型D，其特征在于，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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°和27.8±0.2°。
  18. 根据权利要求17所述的德罗格韦钠盐的晶型D，其特征在于，所述晶型D以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
    Figure PCTCN2015074293-appb-100009
    Figure PCTCN2015074293-appb-100010
  19. 根据权利要求16～18中任一项所述德罗格韦钠盐的晶型D，其特征在于，所述晶型D的傅里叶红外光谱在波数为2922、1636、1621、1531、1504、1425、1317、1280、1254、1198、1110、964、858和744cm-1处具有特征峰。
  20. 一种权利要求16～19中任一项所述的德罗格韦钠盐的晶型D的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)将德罗格韦钠盐的正丁醇溶剂化物晶型C以5～20℃/分钟的升温速率从室温升温至脱溶剂温度150℃，在150℃下保持15～35分钟至完全脱去溶剂，然后以5～20℃/分钟的冷却速率冷却至室温，得到所述晶型D；
    优选地，所述保持的时间为20～35分钟，更优选为20～30分钟；
    优选地，所述升温速率为5～10℃/分钟；
    优选地，所述冷却速率为10～20℃/分钟；
    (2)将德罗格韦钠盐的正丁醇溶剂化物晶型C在130～150℃的环境中放置25～40分钟至完全脱去溶剂，再直接置于室温下，得到所述晶型D；
    优选地，所述环境的温度为140～150℃；
    优选地，所述放置的时间为25～35分钟。
  21. 结构式如下所示的德罗格韦钠盐的三氟乙醇溶剂化物晶型E，
    Figure PCTCN2015074293-appb-100011
    其特征在于，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：6.4±0.2°、6.9±0.2°、11.2±0.2°、11.7±0.2°、19.2±0.2°和20.9±0.2°。
  22. 根据权利要求21所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E，其特征在于，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：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和27.9±0.2°。
  23. 根据权利要求22所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E，其特征在于，所述晶型E以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰及相对强度：
    Figure PCTCN2015074293-appb-100012
  24. 根据权利要求21～23中任一项所述德罗格韦钠盐的三氟乙醇溶剂化物晶型E，其特征在于，所述晶型E的傅里叶红外光谱在波数为3419、3076、1641、1536、1503、1424、1321、1282、1258、1069、1023、963、763和722cm-1处具有特征峰。
  25. 一种权利要求21～24中任一项所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)将德罗格韦钠盐在三氟乙醇或三氟乙醇与有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自C1～C4醇、C4～C5酯、乙腈或其混合物，再自然挥发析晶，得到所述晶型E；
    优选地，所述有机溶剂选自乙醇、乙酸乙酯或乙腈；
    优选地，所述三氟乙醇与有机溶剂的体积比为1:1～4:1，更优选为1:1～2:1；
    优选地，所述制备方法的操作温度为20～60℃，更优选为30～50℃；
    优选地，所述析晶的时间为1～5天，更优选为1～3天；
    优选地，所述德罗格韦钠盐溶液的浓度为德罗格韦钠盐在三氟乙醇或所述混合溶剂中溶解度的0.2～1倍，优选为0.5～1倍，更优选为0.8～1倍；
    (2)向德罗格韦钠盐的三氟乙醇溶液中添加抗溶剂，其中所述抗溶剂选自C1～C4醇、C4～C5酯、异丙醚、乙腈、甲苯或其混合物，搅拌析晶，将析出的晶体分离、干燥，得到所述晶型E；
    优选地，所述抗溶剂选自乙醇、乙酸乙酯或乙腈；
    优选地，所述抗溶剂的体积为三氟乙醇体积的5～20倍，更优选为10～15倍；
    优选地，所述析晶的温度为10～60℃，更优选为室温；
    优选地，所述析晶的时间为1～24小时，更优选为1～5小时；
    优选地，所述德罗格韦钠盐溶液的浓度为析晶温度下德罗格韦钠盐在三氟乙醇中溶解度的0.2～1倍，更优选为0.5～1倍；
    优选地，所述干燥的温度为5～30℃，更优选为20～30℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
  26. 一种药物组合物，其包含治疗和/或预防有效量的药物活性成分选自权利要求1～4中任一项所述的德罗格韦钠盐的晶型A、根据权利要求5所述制备方法得到的德罗格韦钠盐的晶型A、权利要求6～9中任一项所述的德罗格韦钠盐的一水合物晶型B、根据权利要求10所述制备方法得到的德罗格韦钠盐的一水合物晶型B、权利要求11～14中任一项所述的德罗格韦钠盐的正丁醇溶剂化物晶型C、根据权利要求15所述制备方法得到的德罗格韦钠盐的正丁醇溶剂化物晶型C、权利要求16～19中任一项所述的德罗格韦钠盐的晶型D、根据权利要求20所述制备方法得到的德罗格韦钠盐的晶型D、权利要求21～24中任一项所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E或根据权利要求25所述制备方法得到的德罗格韦钠盐的三氟乙醇溶剂化物晶型E，以及至少一种药学上可接受的载体或助剂。
  27. 权利要求1～4中任一项所述的德罗格韦钠盐的晶型A、根据权利要求5所述制备方法得到的德罗格韦钠盐的晶型A、权利要求6～9中任一项所述的德罗格韦钠盐的一水合物晶型B、根据权利要求10所述制备方法得到的德罗格韦钠盐的一水合物晶型B、权利要求11～14中任一项所述的德罗格韦钠盐的正丁醇溶剂化物晶型C、根据权利要求15所述制备方法得到的德罗格韦钠盐的正丁醇溶剂化物晶型C、权利要求16～19中任一项所述的德罗格韦钠盐的晶型D、根据权利要求20所述制备方法得到的德罗格韦钠盐的晶型D、权利要求21～24中任一项所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E、或根据权利要求25所述制备方法得到的德罗格韦钠盐的三氟乙醇溶剂化物晶型E，在制备治疗和/或预防HIV-1感染的药物中的用途。
  28. 一种治疗和/或预防HIV-1感染的方法，所述方法包括给与需要的患者治疗和/或预防有效量的选自权利要求1～4中任一项所述的德罗格韦钠盐的晶型A、根据权利要求5所述制备方法得到的德罗格韦钠盐的晶型A、权利要求6～9中任一项所述的德罗格韦钠盐的一水合物晶型B、根据权利要求10所述制备方法得到的德罗格韦钠盐的晶型B、权利要求11～14中任一项所述的德罗格韦钠盐的正丁醇溶剂化物晶型C、根据权利要求15所述制备方法得到的德罗格韦钠盐的晶型C、权利要求16～19中任一项所述的德罗格韦钠盐的晶型D、根据权利要求20所述制备方法得到的德罗格韦钠盐的晶型D、权利要求21～24中任一项所述的德罗格韦钠盐的三氟乙醇溶剂化物晶型E、根据权利要求25所述制备方法得到的德罗格韦钠盐的晶型E或权利要求26所述的药物组合物。
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