WO2017097085A1 - 一种ahu-377和缬沙坦三钠盐共晶水合物晶型ii的制备方法 - Google Patents

一种ahu-377和缬沙坦三钠盐共晶水合物晶型ii的制备方法 Download PDF

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WO2017097085A1
WO2017097085A1 PCT/CN2016/105335 CN2016105335W WO2017097085A1 WO 2017097085 A1 WO2017097085 A1 WO 2017097085A1 CN 2016105335 W CN2016105335 W CN 2016105335W WO 2017097085 A1 WO2017097085 A1 WO 2017097085A1
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solvent
preparation
crystal form
ahu
water
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PCT/CN2016/105335
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English (en)
French (fr)
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陈敏华
张炎锋
张良
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苏州晶云药物科技有限公司
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Priority to MX2018006969A priority Critical patent/MX2018006969A/es
Priority to KR1020187019105A priority patent/KR102070392B1/ko
Priority to EP16872277.5A priority patent/EP3385256B1/en
Priority to PL16872277T priority patent/PL3385256T3/pl
Priority to JP2018529268A priority patent/JP6628884B2/ja
Priority to CA3007864A priority patent/CA3007864C/en
Priority to US16/060,909 priority patent/US10442775B2/en
Priority to ES16872277T priority patent/ES2862204T3/es
Priority to AU2016368863A priority patent/AU2016368863B2/en
Publication of WO2017097085A1 publication Critical patent/WO2017097085A1/zh
Priority to IL259871A priority patent/IL259871A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the invention relates to a preparation method of AHU-377 and valsartan trisodium salt eutectic hydrate.
  • Heart failure is a debilitating and fatal disease that prevents the heart from pumping enough blood to supply the body, causing a series of symptoms such as difficulty breathing and fatigue, which significantly affects the patient's quality of life.
  • LCZ696 is a drug for the treatment of heart failure developed by Novartis.
  • the generic name for LCZ696 is Valsartan/Sacubitril, trade name: Entresto, LCZ-696A, HY-18204A, Valsartan/AHU-377, CAS accession number: 936623-90- 4 [Valsartan (137862-53-4), Sacubitril (149709-62-6)].
  • LCZ696 is a dual-effect angiotensin receptor enkephalinase inhibitor with a unique mode of action that is thought to reduce strain in failing hearts.
  • LCZ696 enhances the body's natural defenses against heart failure while increasing the levels of natriuretic peptides and other endogenous vasoactive peptides and inhibiting the renin-angiotensin-aldosterone system (RAAS).
  • LCZ696 combines Novartis's hypertension drug (Diovan, generic name: valsartan) and the experimental drug AHU-377.
  • AHU-377 blocks the mechanism of action of two peptides that are responsible for lowering blood pressure, while Diovan improves vasodilation and stimulates the body to excrete sodium and water.
  • the safety threshold for cardiovascular drugs is extremely high, and LCZ696 even shows a higher safety than conventional drugs.
  • LCZ696 is a eutectic hydrate of AHU-377 and valsartan trisodium salt, specifically the crystalline form of AHU-377 and valsartan trisodium salt hemipentahydrate, and the Chinese invention patent ZL200680001733.0 held by Novartis. Its structure, crystal form, preparation method and effect are described in detail.
  • the simplified structure of the LCZ696 is as follows:
  • the object of the present invention is to provide a preparation method of AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II, which can obtain new eutectic hydrate of AHU-377 and valsartan trisodium salt
  • the crystalline form is designated as Form II in the present invention.
  • the present invention adopts the following technical solutions:
  • a method for preparing AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II the X-ray powder diffraction pattern (CuK ⁇ radiation) of the crystal form II is 4.3° ⁇ 0.2°, 5.0° at 2theta There are characteristic peaks at ⁇ 0.2° and 12.8° ⁇ 0.2°, and the preparation method includes the following steps:
  • Step 1 preparing a clear solution containing AHU-377 and valsartan trisodium salt complex, wherein the solvent of the clear solution comprises a first solvent and a second solvent, the first solvent being the inverse of the target product Form II a solvent and capable of azeotroping with water, the second solvent being a positive solvent of the target product Form II, and the second solvent having a boiling point lower than the first solvent;
  • Step 2 The clear solution obtained in the step 1 is evaporated under reduced pressure under a vacuum condition or a nitrogen purge to remove the second solvent and water in the system;
  • Step 3 mixing the system after the step 2 with water, a third solvent and a seed crystal of the selective crystal form II, stirring and crystallization, filtering, washing and drying to obtain the crystal form II, wherein the third solvent is An anti-solvent that is miscible with the first solvent and miscible with water and is the target product Form II.
  • the "positive solvent” means a solvent which is soluble or soluble to Form II;
  • Antisolvent means a solvent that is poorly soluble (insoluble) or sparingly soluble in Form II.
  • the “miscible” as used in the present invention means that the two solvents can be dissolved in any ratio.
  • the “third solvent can be miscible with water” as used in the present invention means that water has a certain solubility in the third solvent and can be fused with the third solvent, and preferably the mass content of water in the third solvent is >0.5% ( That is, at least 0.5 g of water can be fused in 100 g of the third solvent.
  • step 3 water is first mixed with a third solvent, and then the mixture is added to the system which has been subjected to the step 2 to be stirred and crystallized.
  • step 3 seed crystals are first added to the system passing through step 2, and then a mixture of water and a third solvent is added.
  • the embodiment of the step 3 is: adding the seed crystal of the crystal form II to the system passing through the step 2, stirring and dispersing the seed crystal to form a seed bed, and mixing the water with the third solvent, Adding to the seed bed, stirring and crystallization, filtering, washing and drying to obtain the target product Form II.
  • the seed crystal is first ultrasonically dispersed in the first solvent, and then added to the system passing through the step 2.
  • a mixture of water and a third solvent is added to the seed bed at a constant rate, and after completion, the stirring is maintained for 2 to 4 hours.
  • the embodiment of the step 3 is: adding water, a third solvent to the system passing through the step 2, stirring and crystallization, filtering, washing, and drying to obtain the target product crystal form II.
  • the volume ratio of water to the third solvent is 1:100 to 200.
  • step 3 it is preferably washed with a third solvent such as ethyl acetate. Drying is preferably carried out under vacuum at a temperature not higher than 40 °C.
  • Form II can be obtained by the two methods of adding or not seeding the present invention as described above.
  • the first type of seed crystal addition is more preferable.
  • the seed crystal is added and induced, and the crystal obtained has a larger particle size than the crystal seed-free solution, and is not easily bonded and agglomerated, and the powder has good fluidity.
  • the suitable seed dosage is 5% by weight or more, preferably 5% to 15%, more preferably 6% to 15%, still more preferably 8% to 12%, and still more preferably the theoretical yield of the target crystal form II. 9% to 11%, most preferably 10%.
  • the seed crystal may be a seed crystal of Form II obtained by other methods (which will be described in the following examples), or may be a cyclic coating of the product obtained by the process of the present invention.
  • the first solvent may be, for example, a combination of any one or more of toluene, xylene, cyclohexane, isopropyl acetate, methyl isobutyl ketone, and the like.
  • the second solvent may be, for example, a combination of any one or more of methanol, ethanol, and the like.
  • the third solvent may be, for example, a combination of any one or more of ethyl acetate, acetone, 2-butanone, isopropyl acetate, and methyl isobutyl ketone.
  • the first solvent is toluene or a combination of toluene and one or more of xylene, cyclohexane, isopropyl acetate, methyl isobutyl ketone
  • the second solvent is methanol.
  • the third solvent being a combination of one or more selected from the group consisting of ethyl acetate, acetone, 2-butanone, isopropyl acetate, and methyl isobutyl ketone.
  • the first solvent is most preferably toluene, and in addition to satisfying the basic requirements of the present invention for the first solvent, toluene is more advantageous than other solvents to stably obtain crystal form II which is more pure and fluid.
  • the second solvent is more preferably ethanol, and a crystal form II product having a higher chemical purity can be obtained than with methanol.
  • the volume ratio of the first solvent to the second solvent is preferably from 1:0.02 to 0.2, more preferably from 1:0.05 to 0.15.
  • AHU-377 and valsartan may be uniformly dispersed in a first solvent to obtain a dispersion, sodium hydroxide is added to a second solvent to obtain a sodium hydroxide solution, and then dispersed.
  • the liquid was mixed with a sodium hydroxide solution to obtain a clear solution.
  • the mass concentration of the sodium hydroxide solution is controlled to be from 5 wt% to 30 wt%, preferably from 10 wt% to 20 wt%.
  • the molar ratio of AHU-377, valsartan, and sodium hydroxide is 1.00 to 1.05:1:2.95 to 3.
  • the molar ratio of AHU-377, valsartan, and sodium hydroxide is from 1:0.95 to 1:2.95 to 3.
  • the AHU-377 and the valsartan trisodium salt complex may be dissolved in a mixed solvent of the first solvent and the second solvent to obtain the clear solution.
  • the AHU-377 and valsartan trisodium salt complex may be a complex composed of AHU-377 and valsartan trisodium salt through hydrogen bonding (not limited to crystal form), and may be AHU-377.
  • the free acid or its sodium salt, and the valsartan free acid or its sodium salt, as long as the ratio of AHU-377, valsartan and sodium ions is close to 1:1:3. .
  • the solution is filtered if necessary.
  • the temperature at which the reduced pressure evaporation is controlled does not exceed 50 °C.
  • the second solvent and water can be removed as best as possible, but this is not a requirement for obtaining Form II.
  • it is sufficient to evaporate to a ratio of the second solvent and water in the system of less than 0.1% by weight, although in practice, the second solvent and water content in the system can be only a few to several tens of ppm by evaporation under reduced pressure.
  • the volume of the first solvent is reduced compared to the initial volume, and for this purpose, it is preferred to add the first solvent after evaporation (i.e. after step 2, before step 3).
  • the first solvent is added to a volume of 0.5 to 1.5 times, more preferably 0.7 to 1.2 times, of the initial volume before evaporation.
  • the first solvent is added to the initial volume prior to evaporation.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form II obtained according to the method of the present invention has a characteristic peak at a 2theta value of 10.9 ° ⁇ 0.2 ° in addition to the aforementioned characteristic peak.
  • the X-ray powder diffraction pattern of the Form II can also be 5.8° ⁇ 0.2°, 5.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.5° ⁇ 0.2° at 2theta values and One or more of 20.1 ° ⁇ 0.2 ° has a characteristic peak.
  • the X-ray powder diffraction pattern of Form II is at a value of 4.3 ° ⁇ 0.2 °, 5.0 ° ⁇ 0.2 °, 12.8 ° ⁇ 0.2 °, 10.9 ° ⁇ 0.2 °, 14.6 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II has a value of 4.3° ⁇ 0.2°, 5.0° ⁇ 0.2°, 12.8° ⁇ 0.2°, 10.9° ⁇ 0.2°, 14.6 ⁇ 0.2° at 2theta. It has a characteristic peak at 18.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II has a value of 4.3 ° ⁇ 0.2 °, 5.0 ° ⁇ 0.2 °, 12.8 ° ⁇ 0.2 °, 10.9 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2. Characteristic peaks are found at °, 18.9 ° ⁇ 0.2 °, 5.5 ° ⁇ 0.2 °, 5.8 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, and 20.1 ° ⁇ 0.2 °.
  • Form II is a hydrate.
  • Form II packed in two layers of low density polyethylene bags and one layer of aluminum foil composite film bag
  • Form II is stable at 40 ° C, 75% RH for one month
  • tablets containing Form II placed at high In the density polyethylene bottle, the crystal form is stable at 25 ° C and 60% RH for three months, and the crystal form is stable at 40 ° C and 75% RH for one month.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending 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. It is particularly important to note that 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.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • the present invention has the following advantages compared with the prior art:
  • the crystal form II of the present invention is different from the existing crystal form and has the advantage of better powder flowability than the existing crystal form, but it is difficult to pass conventional crystallization ideas and methods (such as cooling, anti- Obtained by solvent addition, salt formation reaction crystallization, etc., the method of the invention can prepare the crystal form II, and the process is stable Controllable, the prepared crystal form II product has high chemical purity and crystal form purity, good fluidity, and the process can be enlarged and meet the needs of large-scale production.
  • Example 1 is an XRPD pattern of Form II obtained in Example 1;
  • Example 2 is a TGA diagram of Form II obtained in Example 1;
  • Figure 3 is an optical micrograph of Form II obtained in Example 3.
  • Example 4 is an optical micrograph of Form II obtained in Example 4.
  • Figure 5 is an XRPD pattern of Form II obtained in Example 5.
  • Fig. 6 is a photomicrograph of the crystal form II obtained in Example 5.
  • the traditional crystallization ideas usually include cooling, evaporation, anti-solvent addition, reaction crystallization, etc.
  • it is difficult to prepare Form II by conventional crystallization methods such as cooling, evaporation and anti-solvent addition.
  • Natural volatilization under certain conditions may result in Form II.
  • this natural volatilization method can only be prepared on a small scale in the laboratory, and the open volatilization method is limited by the influence of air humidity and cannot be guaranteed in different environments. It is stably prepared under humidity, and most of the solvents used, such as toluene and methanol, naturally volatilize under open conditions and seriously pollute the air environment.
  • the innovation of the invention adopts the "hydration reaction crystallization” scheme, which is a new idea, and makes clever use of "the crystallization water is a necessary condition for the formation of AHU-377 and valsartan trisodium salt eutectic (regardless of which crystal form) This feature, crystallization in the absence of a positive solvent to ensure that the target Form II can remain stable throughout the process.
  • the selection of the first solvent, the second solvent and the third solvent is very critical, wherein:
  • the first solvent needs to have the following three key characteristics: 1) the boiling point is higher than the second solvent, so that it can be used to achieve the evaporation of the second solvent in the system; 2) azeotrope with water, can achieve the moisture in the system Evaporation; 3)
  • the target product, Form II is kinetically stable and is not susceptible to crystal transformation.
  • the most typical first solvent is toluene.
  • the second solvent needs to have the following two key characteristics: 1) good solubility to the target product crystal form II; 2) lower boiling point than the first solvent, and easy to be removed by evaporation under reduced pressure in the mixed system of the two.
  • a suitable second solvent may be selected from methanol or ethanol or a mixture of the two.
  • the third solvent needs to have the following three key characteristics: 1) the anti-solvent for the crystal form II, so that the crystal form II is stable in kinetics, and is not easy to undergo crystal transformation; 2) can be completely or partially miscible with water; ) can be miscible with the first solvent (such as toluene). Since the water and the first solvent are mutually insoluble, for example, when the first solvent is toluene, it is not preferable to replenish water in the form of pure water droplets in the process, and the third solvent serves as a carrier solvent for hydrating.
  • a suitable third solvent may be selected from a combination of one or more of ethyl acetate, acetone, 2-butanone, isopropyl acetate, and methyl isobutyl ketone.
  • the selection of the amount of seed crystal addition is also important, although it does not affect the formation of Form II, but the amount of addition affects the particle morphology and particle size of Form II, thereby affecting its fluidity and filtration. performance.
  • the most preferable range of the seed crystal addition amount is 8% to 12%. Within this range, the product particle form is very complete, the particle size is uniform, the fluidity is good, and it is easy to filter.
  • the ratio of the seed crystal addition amount is 5%, the crystal form II can be stably formed, but the fine particles of the product are greatly increased, the filter pores are easily clogged during filtration, the efficiency is affected, and the fluidity of the product is also deteriorated.
  • the invention is further illustrated by the following examples, but is not intended to limit the scope of the invention.
  • the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the term "about” preceding the temperature value means that it is close to the temperature value, generally plus or minus 2 °C.
  • “about 50 ° C” includes a range of 48 to 52 ° C. It is indicated that the "%" of the content means the mass percentage unless otherwise specified.
  • TGA Thermogravimetric analysis.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the seed crystal of Form II can be obtained by the following steps:
  • a method for preparing AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II comprising the following steps:
  • Step 1 can also be obtained by directly dissolving 50 g of AHU-377 and valsartan trisodium salt complex (crystal form) directly in a mixed solvent of 50 mL of methanol and 1 L of toluene).
  • Step 2 The clear solution obtained in step 1 is evaporated under reduced pressure at a temperature of 50 ° C. After evaporation of about 300 mL of solvent, evaporation is stopped, and an equal volume of toluene is added to the initial volume before evaporation (in this case, methanol in the solution) And water content are below 0.1%);
  • Step 3a Weigh 5.0 g of seed crystal of Form II (addition amount is 10% of the theoretical yield of the target crystal form), ultrasonically disperse in 50 mL of toluene, add to the solution of Step 2, stir to disperse the seed crystal Forming a seed bed;
  • Step 3b After mixing 3.33 mL of water and 500 mL of ethyl acetate, the mixture was uniformly added to the above seed bed for 1 hour. After the addition was completed, the system was maintained under stirring for 2 h, filtered and washed with ethyl acetate. Finally, Vacuum drying at a temperature of 40 ° C gave the target product Form II.
  • the TGA pattern of Form II is shown in Figure 2 with a weight loss gradient of about 6.68% when heated to 150 °C.
  • a method for preparing AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II comprising the following steps:
  • Step 1 Weigh 4.25 g of AHU-377 and 4.64 g of valsartan, add 200 mL of toluene, stir and uniformly disperse to obtain a dispersion; weigh 8.97 g of a 13.7% sodium hydroxide methanol solution and add it dropwise. In the dispersion, a clear solution was obtained.
  • Step 2 Evaporate the solvent from the clear solution obtained in step 1 by nitrogen purge at room temperature. After evaporating about 75 mL of solvent, stop evaporating and add an equal volume of toluene to the initial volume before evaporation (in this case, methanol and water in the solution). The content is controlled below 0.1%);
  • Step 3a Weigh 1.0 g of seed crystal of Form II (addition amount is 10% of theoretical yield of target crystal form), ultrasonically disperse in 10 mL of toluene, add to the solution of step 2, stir to disperse the seed crystal Forming a seed bed;
  • Step 3b After mixing 665 ⁇ L of water with 100 mL of ethyl acetate, the solution was added to the above seed bed at a constant rate for 1 hour. After the addition was completed, the system was maintained under stirring for 3 hours, filtered under nitrogen, and dried under vacuum at 40 ° C. , the target product Form II is obtained.
  • a method for preparing AHU-377 and valsartan trisodium salt eutectic hydrate crystal form II comprising the following steps:
  • Step 1 Weigh 0.217g of AHU-377 and 0.233g of valsartan, add 10mL of toluene, stir and disperse uniformly to obtain a dispersion; weigh 4.459g of sodium hydroxide methanol solution with a mass concentration of 13.68%, and add it dropwise In the dispersion, the system was dissolved after the addition was completed.
  • Step 2 Evaporate the solvent from the clear solution obtained in step 1 by purging nitrogen at room temperature. When 4 mL of solvent is distilled off, the evaporation is stopped, and an equal volume of toluene is added to the initial volume before evaporation (in this case, methanol and water in the solution). The content is controlled below 0.1%);
  • Step 3a Weigh 50.6 mg of seed crystal of Form II (addition amount is 10% of the theoretical yield of the target crystal form), ultrasonically disperse in 500 ⁇ L of toluene, add to the solution of step 2, and stir to disperse the seed crystal. Forming a seed bed;
  • Step 3b After mixing 33 ⁇ L of water and 5 mL of ethyl acetate, the mixture was uniformly added to the above-mentioned seed bed for 1 hour. After the addition was completed, the system was maintained under stirring for 4 hours, filtered and dried under vacuum at 40 ° C to obtain the target product. Form II.
  • This example is basically the same as in Example 3, except that the seed crystal is added in an amount of 5%.
  • the particles of Form II obtained in Example 3 and Example 4 were observed under a microscope, and the results are shown in Fig. 3 and Fig. 4, respectively. Comparing Fig. 3 and Fig. 4, the use of 10% seed crystals can make the final product particles complete in morphology, uniform in particle size, good in fluidity and easy to filter. In contrast, under the condition of using 5% seed crystal, although the crystal form II can be stably obtained, the fine particles in the product are greatly increased, the filter pores are more likely to be clogged during filtration, the efficiency is affected, and the fluidity of the product is relatively changed. difference.
  • This example is basically the same as in Example 3, except that no seed crystals are added during the process.
  • Step 1 Weigh 0.217g AHU-377 and 0.233g valsartan, add 10mL of toluene, stir and disperse evenly to obtain a dispersion; weigh 4.459g of sodium hydroxide methanol solution with a mass concentration of 13.68%. This was added dropwise to the dispersion, and the system was dissolved after the completion of the dropwise addition.
  • Step 2 Evaporate the solvent from the clear solution obtained in step 1 by purging nitrogen at room temperature. When 4 mL of solvent is distilled off, the evaporation is stopped, and an equal volume of toluene is added to the initial volume before evaporation (in this case, methanol and water in the solution). The content is controlled below 0.1%);
  • Step 3 33 ⁇ L of water and 5 mL of ethyl acetate were uniformly mixed, and added dropwise to the system after the step 2, the time was 1 h. After the completion of the dropwise addition, the system was maintained under stirring for 4 hours, filtered and dried under vacuum at 40 ° C to obtain Target product Form II.
  • the product obtained in this example has the same crystal form II as the product of Example 3, and its XRPD pattern is shown in Fig. 5, and its polarizing microscope chart is shown in Fig. 6.
  • a method for preparing AHU-377 and valsartan trisodium salt co-crystal hydrate crystal form II comprising the following steps:
  • Step 1 Weigh 21.77g AHU-377 and 22.70g valsartan, add 1L of toluene, stir and evenly disperse to obtain a dispersion, record the initial volume; weigh 128.89g of sodium hydroxide ethanol solution with a mass concentration of 4.814%, This was added dropwise to the dispersion to obtain a clear solution.
  • Step 2 The clear solution obtained in the step 1 is concentrated under reduced pressure at 50 ° C. After distilling off about 500-600 mL of the solvent, the concentration is stopped, the temperature is lowered to 20 ° C, and 450 mL of toluene is added to the initial volume in the step 1;
  • Step 3a Weigh 5.01 g of crystal form of crystal form II (addition amount is 10% of the target product), ultrasonically disperse in 50 mL of toluene, add to the solution of step 2, stir to disperse the seed crystal to form a seed bed;
  • Step 3b After mixing 3.3 mL of water and 500 mL of ethyl acetate, the mixture was uniformly added to the above-mentioned seed bed for 1 hour. After the completion of the dropwise addition, the system was maintained and stirred for 2 hours, filtered, and the wet product was rinsed with 150 mL of ethyl acetate. Drying at 30 ° C under vacuum gave the desired product Form II.
  • a method for preparing AHU-377 and valsartan trisodium salt co-crystal hydrate crystal form II comprising the following steps:
  • Step 1 Weigh 177.62g AHU-377 and 181.62g valsartan, add 4L of toluene, stir and evenly disperse to obtain a dispersion; weigh 49.64g of sodium hydroxide dissolved in 1.2L of ethanol to form a solution, the hydrogen and oxygen A solution of sodium chloride in ethanol is added dropwise to the dispersion to obtain a clear solution.
  • the solution was transferred to a 20 L jacketed reaction vessel and diluted with 4 L of toluene (total 8 L of toluene).
  • Step 2 The clear solution obtained in step 1 is concentrated under reduced pressure at 50 ° C. When the remaining volume is about 5 L, the concentration is stopped, the temperature is lowered to 20 ° C, and 3 L of toluene is added to a total solution volume of about 8 L;
  • Step 3a Weigh 40.0 g of crystal form II crystal form (addition amount is 10% of the target product), after ultrasonic dispersion in 400 mL of toluene, add to the solution of step 2, stir to disperse the seed crystal to form a seed bed;
  • Step 3b After mixing 26.4 g of water and 4 L of ethyl acetate, the mixture was uniformly added to the above seed bed for 1 hour. After the addition was completed, the system was maintained under stirring for 1.5 h, filtered and rinsed with 1.5 L of ethyl acetate. The product was vacuum dried at 30 ° C to obtain the target product Form II.
  • a method for preparing AHU-377 and valsartan trisodium salt co-crystal hydrate crystal form II comprising the following steps:
  • Step 1 Weigh 178g of AHU-377 and 181g of valsartan, stir and disperse in 4L of jacketed reaction kettle with 4L of toluene; weigh 49.64g of sodium hydroxide dissolved in 1.2L of ethanol to form a solution, the ethanol solution of sodium hydroxide It was added dropwise to the kettle and the reaction gave a clear solution. Dilute with 4 L of toluene (total 8 L of toluene).
  • Step 2 The clear solution obtained in step 1 is concentrated under reduced pressure at 50 ° C. When the remaining volume is about 5 L, the concentration is stopped, the temperature is lowered to 20 ° C, and 3.5 L of toluene is added to a total solution volume of about 8.5 L;
  • Step 3a Weigh 40.1 g of crystal form II crystal form (addition amount is 10% of the target product), ultrasonically disperse in 400 mL of toluene, add to the solution of step 2, stir to disperse the seed crystal to form a seed bed;
  • Step 3b After mixing 26.4 g of water and 4 L of ethyl acetate, the mixture was uniformly added to the above seed bed for 1 hour. After the addition was completed, the system was maintained under stirring for 3.5 h, filtered and rinsed with 1.5 L of ethyl acetate. The product was vacuum dried at 30 ° C to obtain the target product Form II.
  • a method for preparing AHU-377 and valsartan trisodium salt co-crystal hydrate crystal form II comprising the following steps:
  • Step 2 The clear solution obtained in step 1 is concentrated under reduced pressure at 50 ° C, and the concentration is stopped when the remaining volume is about 7 L, and 3 L of toluene is added to the total solution volume of about 10 L, and the temperature is lowered to room temperature ( ⁇ 20 ° C);
  • Step 3a Weigh 50g of crystal form II crystal form (addition amount is 10% of the target product), after being sonicated in 500mL of toluene for 1min, add to the solution of step 2, stir to disperse the seed crystal to form a seed bed;
  • Step 3b After mixing 32 g of water and 5 L of ethyl acetate, the mixture was uniformly added to the above-mentioned seed bed for 1 hour. After the addition was completed, the system was maintained under stirring for 3 hours, filtered, and the wet product was rinsed with 2 L of ethyl acetate. Drying at 30 ° C under vacuum gave the desired product Form II.
  • the XRPD and TGA tests were carried out on the crystal form II of 7 batches obtained according to the method and conditions of the present invention. The results showed that the crystal form II was obtained, and the weight loss was sorted from small to large as follows: 5.60%; 6.18% ;6.68%; 6.68%; 8.06%; 9.48%; 9.68%.

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Abstract

本发明公开了一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，首先获得AHU-377和缬沙坦三钠盐复合物的澄清溶液，该澄清溶液的溶剂由目标产物晶型II的反溶剂和正溶剂构成，且正溶剂的沸点低于反溶剂；其次，通过在密闭条件下蒸发除去体系中的正溶剂和水；最后，选择性地加入晶型II的晶种并补加水和载体溶剂的混合物，进行搅拌析晶。本发明的方法能够制备出晶型II，并且其工艺过程稳定可控，制备的晶型II产品化学纯度和晶型纯度高，流动性好，工艺可实现放大并满足规模化生产的需求。

Description

一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法 技术领域
本发明涉及一种AHU-377和缬沙坦三钠盐共晶水合物的制备方法。
背景技术
心力衰竭(HF)是一种令人衰弱的致命性疾病，它使心脏不能泵出足够的血液供应全身，由此引发呼吸困难、疲劳等一系列症状，显著影响患者的生活质量。
LCZ696是由诺华制药研发的一种治疗心衰药物，LCZ696的通用名称为Valsartan/Sacubitril，商品名：Entresto，LCZ-696A，HY-18204A，Valsartan/AHU-377，CAS登录号：936623-90-4[Valsartan(137862-53-4)，Sacubitril(149709-62-6)]。LCZ696是一种双效血管紧张素受体脑啡肽酶抑制剂，具有独特的作用模式，被认为能够降低衰竭心脏的应变。LCZ696可增强机体对抗心衰的自然防御力，同时可增加利钠肽和其他内源性血管活性肽的水平，并抑制肾素-血管紧张素-醛固酮系统(RAAS)。LCZ696结合了诺华的高血压药物代文(Diovan，通用名：缬沙坦)和实验性药物AHU-377。AHU-377可阻断威胁负责降低血压的2种多肽的作用机制，Diovan则可改善血管舒张，刺激身体排泄钠和水。心血管类药物的安全性门槛极高，而LCZ696甚至表现出了超越常规药物的更高安全性。
LCZ696是AHU-377和缬沙坦三钠盐共晶水合物，具体为AHU-377和缬沙坦三钠盐半五水合物的结晶形式，在诺华公司所持有的中国发明专利ZL200680001733.0中详细描述了其结构、晶型和制备方法以及作用。LCZ696的简化结构如下：
Figure PCTCN2016105335-appb-000001
发明内容
本发明的目的是提供一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，该方法可以获得AHU-377和缬沙坦三钠盐共晶水合物的新的结晶形式，本发明中命名为晶型II。
为实现上述目的，本发明采取如下技术方案：
一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，所述晶型II的X射线粉末衍射图(CuKα辐射)在2theta值为4.3°±0.2°、5.0°±0.2°、12.8°±0.2°处具有特征峰，所述制备方法包括以下步骤：
步骤1：制备含有AHU-377和缬沙坦三钠盐复合物的澄清溶液，其中所述澄清溶液的溶剂包含第一溶剂和第二溶剂，所述第一溶剂是目标产物晶型II的反溶剂且能够与水共沸，所述第二溶剂是目标产物晶型II的正溶剂，且所述第二溶剂的沸点低于所述第一溶剂；
步骤2：将步骤1所得澄清溶液在密闭条件下减压蒸发或氮气吹扫蒸发，以除去体系中的第二溶剂和水；以及，
步骤3：将经过步骤2的体系与水、第三溶剂和选择性地晶型II的晶种混合，搅拌析晶，过滤，洗涤，干燥即得所述晶型II，所述第三溶剂为能够与第一溶剂互溶、且能与水混溶，且是目标产物晶型II的反溶剂。
根据本发明，所述的“正溶剂”是指对晶型II易溶或可溶的溶剂；所述的 “反溶剂”是指对晶型II难溶(不溶)或微溶的溶剂。本发明所述的“互溶”是指二种溶剂之间可以任意比例溶解。本发明所述的“第三溶剂能与水混溶”是指水在第三溶剂中具有一定的溶解度而能够与第三溶剂融合，优选水在第三溶剂中的质量含量为＞0.5％(即100g第三溶剂中可以融合至少0.5g的水)。
根据本发明的一个优选方面，步骤3中，先将水与第三溶剂混合，然后将混合物加入到经过步骤2的体系中搅拌析晶。
根据本发明的又一个优选方面，步骤3中，先向经过步骤2的体系中加入晶种，然后加入水与第三溶剂的混合物。
根据本发明的一个方面，步骤3的实施方式为：向经过步骤2的体系中加入晶型II的晶种，并搅拌使晶种分散形成晶种床，另将水与第三溶剂混合后，加入晶种床中，搅拌析晶，过滤，洗涤，干燥即得目标产物晶型II。
优选地，步骤3中，先将晶种在第一溶剂中超声分散后，再加入经过步骤2的体系中。
优选地，将水和第三溶剂的混合物匀速加入到所述晶种床，加毕，维持搅拌熟化2～4h。
根据本发明的又一方面，步骤3的实施方式为：向经过步骤2的体系中加入水、第三溶剂，搅拌析晶，过滤，洗涤，干燥即得目标产物晶型II。
进一步地，上述步骤3中，水与第三溶剂的体积比为1∶100～200。
进一步地，步骤3中，优选采用第三溶剂例如乙酸乙酯进行洗涤。干燥优选在不高于40℃的温度下进行真空干燥。
本发明如上所述的添加晶种或不加晶种这两种方案均可以获得晶型II。其中，以第一种添加晶种的方案更为优选。在第一种方案中，晶种的投加起诱导作用，与不添加晶种的方案相比获得的晶体的粒度更大，不容易粘结团聚，粉体流动性好。且经我们研究发现，当控制合适的晶种投加量时，可以获得颗粒形态更完整、粒度更均一，从而流动性更好、更易过滤的目标产物。所述合适的晶种投加量为目标晶型II理论产量的5wt％以上，优选为5％～15％，更优选为6％～15％，进一步优选为8％～12％，更进一步优选9％～11％，最优选10％。所述的晶种可以是通过其他方法(在以下实施例中将会介绍)获得的晶型II的晶种，也可以是本发明工艺所得产品的循环套用。
根据本发明，第一溶剂可以为例如甲苯、二甲苯、环己烷、乙酸异丙酯、甲基异丁基酮等中的任意一种或多种的组合。第二溶剂可以为例如甲醇、乙醇等中的任意一种或多种的组合。第三溶剂可以为例如乙酸乙酯、丙酮、2-丁酮、乙酸异丙酯以及甲基异丁基酮等中的任意一种或多种的组合。根据本发明的一个具体优选方面，第一溶剂为甲苯或甲苯与二甲苯、环己烷、乙酸异丙酯、甲基异丁基酮中的一种或多种的组合，第二溶剂为甲醇或乙醇或二者的组合，第三溶剂为选自乙酸乙酯、丙酮、2-丁酮、乙酸异丙酯以及甲基异丁基酮中的一种或多种的组合。
根据发明，第一溶剂最优选为甲苯，除了满足本发明对于第一溶剂的基本要求外，甲苯相比其他溶剂更有利于稳定地获得更纯和更好流动性的晶型II。
根据本发明，第二溶剂更优选乙醇，相对于采用甲醇，可以获得化学纯度更高的晶型II产品。
根据本发明，第一溶剂与第二溶剂的体积比优选为1∶0.02～0.2，更优选为1∶0.05～0.15。
根据本发明的一个方面，步骤1中，可以先将AHU-377和缬沙坦用第一溶剂分散均匀得到分散液，将氢氧化钠加入到第二溶剂中获得氢氧化钠溶液，然后将分散液与氢氧化钠溶液混合，获得澄清溶液。一般地，控制氢氧化钠溶液的质量浓度为5wt％～30wt％，优选10wt％～20wt％。
在一个具体实施方式中，制备所述澄清溶液时，AHU-377、缬沙坦以及氢氧化钠三者的投料摩尔比为1.00～1.05∶1∶2.95～3。在又一具体且更优选的实施方式中，制备所述澄清溶液时，AHU-377、缬沙坦以及氢氧化钠三者的投料摩尔比为1∶0.95～1∶2.95～3。
根据本发明的又一方面，步骤1中，可以将AHU-377和缬沙坦三钠盐复合物溶解于第一溶剂和第二溶剂组成的混合溶剂中，即得所述澄清溶液。其中，对于AHU-377和缬沙坦三钠盐复合物没有特别要求，可以是AHU-377和缬沙坦三钠盐通过氢键构成的复合物(不限晶型)，可以是AHU-377的游离酸或其钠盐，和缬沙坦游离酸或其钠盐，只要满足AHU-377、缬沙坦、钠离子的比例接近1∶1∶3。。
优选地，在制备澄清溶液过程中，如有必要，对溶液进行过滤。
优选地，步骤2中，控制所述减压蒸发的温度不超过50℃。
根据本发明，步骤2中，第二溶剂和水能够被尽可能除尽最好，但这不是获得晶型II的必要条件。一般来说，蒸发至体系中第二溶剂和水的含量均低于0.1wt％时即可，虽然实际中可以通过减压蒸发使体系中第二溶剂和水含量只有几个至几十ppm。
根据本发明，步骤2中在蒸发后，第一溶剂的体积比初始体积减少，为此，优选在蒸发后(即步骤2之后、步骤3之前)再补加第一溶剂。优选地，补加第一溶剂至体积为蒸发前的初始体积的0.5～1.5倍，更优选为0.7～1.2倍。在一个具体实施方式中，补加第一溶剂至蒸发前的初始体积。
进一步地，根据本发明的方法所获得的所述晶型II的X射线粉末衍射图(CuKα辐射)除了具有前述特征峰外，还在2theta值10.9°±0.2°处具有特征峰。
更进一步地，所述晶型II的X射线粉末衍射图还可在2theta值5.8°±0.2°、5.5°±0.2°、18.9°±0.2°、14.6°±0.2°、18.5°±0.2°及20.1°±0.2°中的一处或多处具有特征峰。
根据本发明的一个具体方面，晶型II的X射线粉末衍射图在2theta值为4.3°±0.2°、5.0°±0.2°、12.8°±0.2°、10.9°±0.2°、14.6±0.2°处具有特征峰。
根据本发明的又一具体方面，晶型II的X射线粉末衍射图在2theta值为4.3°±0.2°、5.0°±0.2°、12.8°±0.2°、10.9°±0.2°、14.6±0.2°、18.9±0.2°处具有特征峰。
根据本发明的再一个具体方面，晶型II的X射线粉末衍射图在2theta值为4.3°±0.2°、5.0°±0.2°、12.8°±0.2°、10.9°±0.2°、14.6°±0.2°、18.9°±0.2°、5.5°±0.2°、5.8°±0.2°、18.5°±0.2°、20.1°±0.2°处均具有特征峰。
根据本发明的再一个具体方面，晶型II为水合物。
在一个具体的实施例中，晶型II的XRPD图如图1所示。
其他关于本发明晶型II的特点是：
1.对多个批次所得晶型II产品进行分析(TGA)，结果表明，晶型II为水合物，且水的质量含量在5.0％～10.0％之间，集中在5.5～9.5％范围内，更集中在5.5～8.5％范围内，最集中在6.0～7.0％之间。
2.晶型II(经两层低密度聚乙烯袋和一层铝箔复合膜袋包装)在40℃、75％RH条件下放置一个月稳定不变；包含晶型II的片剂(放置在高密度聚乙烯瓶中)在25℃、60％RH条件下放置三个月晶型稳定不变、在40℃、75％RH条件下放置一个月晶型稳定不变。
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，这里所讨论的理化性质可以被表征，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，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明所述晶型II，其不同于现有晶型且与现有的晶型相比具有粉体流动性更好的优势，但其很难通过常规的结晶思路和方法(如降温、反溶剂添加、成盐反应结晶等)获得，本发明方法能够制备出晶型II，并且其工艺过程稳定 可控，制备的晶型II产品化学纯度和晶型纯度高，流动性好，工艺可实现放大并满足规模化生产的需求。
附图说明
图1为实施例1所得晶型II的XRPD图；
图2为实施例1所得晶型II的TGA图；
图3为实施例3所得晶型II的光学显微镜图；
图4为实施例4所得晶型II的光学显微镜图；
图5为实施例5所得晶型II的XRPD图；
图6为实施例5所得晶型II的光学显微镜图。
具体实施方式
传统的结晶思路通常包括降温、蒸发、反溶剂添加、反应结晶等，然而采用传统的降温、蒸发和反溶剂添加等结晶方法都很难制备晶型II。特定条件下的自然挥发或可能得到晶型II，但是，这种自然挥发法只能在在实验室小规模制备得到，而且敞口挥发法受限于空气湿度的影响，不能保证在不同的环境湿度下稳定制备得到，而使用的多数溶剂例如甲苯和甲醇等，在敞口条件下自然挥发会严重污染空气环境。这些问题决定了即便敞口挥发法可以得到晶型II，该方法也难以实现工艺放大和满足规模化生产的要求。
本发明创新采用“补水反应结晶”方案，这是一条新思路，巧妙利用了“结晶水是AHU-377和缬沙坦三钠盐共晶(无论是对于其何种晶型)形成的必要条件”这一特点，在无正溶剂存在的环境下进行结晶，以确保目标晶型II在整个工艺过程中能够保持稳定。
本发明的制备方法中：第一溶剂、第二溶剂以及第三溶剂的选择非常关键，其中：
第一溶剂需要具备以下三个关键性的特点：1)沸点比第二溶剂高，从而可用于实现对体系中第二溶剂的蒸除；2)与水共沸，可以实现对体系中水分的蒸除；3)目标产物晶型II在其中动力学稳定，不易发生晶型转变。最典型的第一溶剂即甲苯。
第二溶剂需要具备以下二个关键性的特点：1)对目标产物晶型II要有好的溶解度；2)沸点低于第一溶剂，容易在二者的混合体系中被减压蒸发除去。考虑到第一溶剂是甲苯的情况下，适合的第二溶剂可以选择甲醇或乙醇或二者的混合物。
第三溶剂需要具备以下三个关键性的特点：1)对晶型II为反溶剂，使得晶型II在其中动力学稳定，不易发生转晶；2)能与水完全或部分混溶；3)可与第一溶剂(如甲苯)互溶。由于水和第一溶剂有不互溶的可能，例如当第一溶剂为甲苯时，因此工艺中不宜以纯水滴加的形式来补水，此处第三溶剂的作用即是作为补水的载体溶剂。在第一溶剂为甲苯的情况下，适合的第三溶剂可以选择乙酸乙酯、丙酮、2-丁酮、乙酸异丙酯以及甲基异丁基酮中的一种或多种的组合。
此外，作为实现本发明的关键要素之一，还必须严格控制减压蒸发后第二溶剂和水被有效除去，这是保证后续补水结晶过程中晶型II不会发生转晶的关键。
本发明中，晶种添加量的选择也是较为重要的，虽然不会对晶型II的形成构成影响，但是添加量的多少会影响晶型II的颗粒形态和粒度，从而影响其流动性和过滤性能。经发明人研究发现，晶种添加量最优选的范围是8％～12％。在该范围内，产品颗粒形态非常完整，粒度均一，流动性好，极易过滤。与此对比，晶种添加量的比例为5％时，晶型II也能稳定形成，但产品的细颗粒会大大增多，过滤时易堵塞滤孔，影响效率，产品的流动性也变差。
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。在温度数值前面的术语“约”表示接近该温度值，一般正负2℃。例如，“约50℃”包括48～52℃的范围。表明含量的“％”在没有特别说明时指的是质量百分含量。
未注明的实验条件为常规条件。
本发明中所用到的名词解释如下：
XRPD：X射线粉末衍射
TGA：热重分析。
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
Figure PCTCN2016105335-appb-000002
1.540598；
Figure PCTCN2016105335-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气。
以下实施例中，晶型II的晶种可通过如下步骤获得：
将1g的AHU-377和缬沙坦三钠盐复合物溶于1mL甲醇和10mL甲苯的混合溶剂，过滤去除不溶杂质后得澄清溶液。将该溶液在室温环境下敞口搅拌自然挥发直至析出大量白色固体(注：环境温度21.1℃；环境相对湿度35.2％)，过滤该沉淀物并将其在40℃下真空干燥至干。
实施例1
一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取21.25gAHU-377和23.20g缬沙坦，加入1L的甲苯后搅拌均匀分散，得分散液；称取45.56g质量浓度为13.5％的氢氧化钠甲醇溶液，将其滴加到分散液中，时间约为1h，滴加完毕后体系溶清(投料摩尔比AHU-377∶缬沙坦∶氢氧化钠＝1∶1.02∶3)，过滤除去潜在的不溶杂质，得到澄清溶液。(说明：步骤1也可以通过直接将AHU-377和缬沙坦三钠盐复合物(晶型不限)50g直接溶解于50mL甲醇和1L甲苯的混合溶剂中得到)。
步骤2：将步骤1所得澄清溶液在密闭条件下、温度50℃下减压蒸发，当蒸出300mL左右溶剂后停止蒸发，补加等体积的甲苯至蒸发前的初始体积(此时溶液中甲醇和水含量均在0.1％以下)；
步骤3a：称取5.0g的晶型II的晶种(添加量是目标晶型理论产量的10％)，在50mL的甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将3.33mL水与500mL乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化2h，过滤并用乙酸乙酯洗涤滤饼，最后在40℃的温度下进行真空干燥，得到目标产品晶型II。
晶型II的XRPD图如图1所示。
晶型II的TGA图如图2所示，在加热至150℃时，具有约6.68％的重量损失梯度。
实施例2
一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取4.25gAHU-377和4.64g缬沙坦，加入200mL的甲苯后搅拌均匀分散，得分散液；称取8.97g质量浓度为13.7％的氢氧化钠甲醇溶液，将其滴加到分散液中，得到澄清溶液。
步骤2：将步骤1所得澄清溶液通过常温下氮气吹扫的方式蒸发溶剂，当蒸出75mL左右溶剂后停止蒸发，补加等体积的甲苯至蒸发前的初始体积(此时溶液中甲醇和水含量均控制在0.1％以下)；
步骤3a：称取1.0g的晶型II的晶种(添加量是目标晶型理论产量的10％)，在10mL的甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将665μL水与100mL乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化3h，氮气保护下过滤，并在40℃下真空干燥，得到目标产品晶型II。
实施例3
一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取0.217gAHU-377和0.233g缬沙坦，加入10mL的甲苯后搅拌均匀分散，得分散液；称取0.459g质量浓度为13.68％的氢氧化钠甲醇溶液，将其滴加到分散液中，滴加完毕后体系溶清。
步骤2：将步骤1所得澄清溶液通过常温下氮气吹扫的方式蒸发溶剂，当蒸出4mL左右溶剂后停止蒸发，补加等体积的甲苯至蒸发前的初始体积(此时溶液中甲醇和水含量均控制在0.1％以下)；
步骤3a：称取50.6mg的晶型II的晶种(添加量是目标晶型理论产量的10％)，在500μL的甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将33μL水与5mL乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化4h，过滤并在40℃下真空干燥，得到目标产品晶型II。
实施例4
本例基本同实施例3，不同的是，晶种的添加量为5％。
对实施例3和实施例4所得晶型II的颗粒进行显微镜观察，结果分别如图3和图4所示。比较图3和图4可见，使用10％的晶种量，可以使最终的产品颗粒形态完整，粒度均一，流动性好，极易过滤。与此对比，使用5％晶种的条件下，虽然也能稳定得到晶型II，但产品中的细颗粒会大大增多，过滤时较易堵塞滤孔，影响效率，产品的流动性也相对变差。
实施例5
本例基本同实施例3，不同的是，过程中不添加任何晶种。
本例具体步骤如下：
步骤1：称取0.217gAHU-377和0.233g缬沙坦，加入10mL的甲苯后搅拌均匀分散，得分散液；称取0.459g质量浓度为13.68％的氢氧化钠甲醇溶液， 将其滴加到分散液中，滴加完毕后体系溶清。
步骤2：将步骤1所得澄清溶液通过常温下氮气吹扫的方式蒸发溶剂，当蒸出4mL左右溶剂后停止蒸发，补加等体积的甲苯至蒸发前的初始体积(此时溶液中甲醇和水含量均控制在0.1％以下)；
步骤3：将33μL水与5mL乙酸乙酯混合均匀后，滴加到经过步骤2的体系中，时间为1h，滴加完毕后，体系维持搅拌熟化4h，过滤并在40℃下真空干燥，得到目标产品晶型II。
本例得到的产品具有与实施例3产品相同的晶型II，其XRPD图如图5所示，其偏光显微镜图如图6所示。
实施例6
一种AHU-377和缬沙坦三钠盐共结晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取21.77gAHU-377和22.70g缬沙坦，加入1L甲苯后搅拌均匀分散，得分散液，记录该初始体积；称取128.89g质量浓度为4.814％的氢氧化钠乙醇溶液，将其滴加到分散液中，得到澄清溶液。
步骤2：将步骤1所得澄清溶液在50℃减压浓缩，当蒸出500～600mL左右溶剂后停止浓缩，降温至20℃，补加450mL甲苯至步骤1中的初始体积；
步骤3a：称取5.01g晶型II的晶种(添加量是目标产物的10％)，在50mL甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将3.3mL水与500mL乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化2h，过滤并用150mL乙酸乙酯淋洗湿品，在30℃下真空干燥，得到目标产品晶型II。
实施例7
一种AHU-377和缬沙坦三钠盐共结晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取177.62gAHU-377和181.62g缬沙坦，加入4L甲苯后搅拌均匀分散，得分散液；称取49.64g氢氧化钠溶于1.2L乙醇配成溶液，将该氢氧 化钠的乙醇溶液滴加到分散液中，反应得到澄清溶液。将溶液转移到20L夹套反应釜中并加入4L甲苯稀释(甲苯共计8L)。
步骤2：将步骤1所得澄清溶液在50℃减压浓缩，当剩余体积在5L左右时停止浓缩，降温至20℃，补加3L甲苯至总溶液体积8L左右；
步骤3a：称取40.0g晶型II的晶种(添加量是目标产物的10％)，在400mL甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将26.4g水与4L乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化1.5h，过滤并用1.5L乙酸乙酯淋洗湿品，在30℃下真空干燥，得到目标产品晶型II。
实施例8
一种AHU-377和缬沙坦三钠盐共结晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取178gAHU-377和181g缬沙坦，用4L甲苯搅拌分散于20L夹套反应釜；称取49.64g氢氧化钠溶于1.2L乙醇配成溶液，将该氢氧化钠的乙醇溶液滴加到釜中，反应得到澄清溶液。补加4L甲苯稀释(甲苯共计8L)。
步骤2：将步骤1所得澄清溶液在50℃减压浓缩，当剩余体积在5L左右时停止浓缩，降温至20℃，补加3.5L甲苯至总溶液体积8.5L左右；
步骤3a：称取40.1g晶型II的晶种(添加量是目标产物的10％)，在400mL甲苯中超声分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将26.4g水与4L乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化3.5h，过滤并用1.5L乙酸乙酯淋洗湿品，在30℃下真空干燥，得到目标产品晶型II。
晶型II的X射线粉末衍射数据如表1所示。
表1
衍射角2θ d值 强度％
4.34 20.35 55.53
5.09 17.36 100.00
5.53 15.99 69.86
5.83 15.15 60.72
7.36 12.01 3.56
8.55 10.34 4.12
9.97 8.87 12.74
10.98 8.05 8.51
11.64 7.60 8.03
12.80 6.91 26.88
13.31 6.65 6.00
13.84 6.40 10.47
14.00 6.33 10.53
14.68 6.03 13.57
15.08 5.87 17.59
16.01 5.53 7.94
16.65 5.33 15.12
17.40 5.10 14.74
17.70 5.01 15.45
18.41 4.82 14.20
19.09 4.65 11.59
19.65 4.52 7.74
20.27 4.38 9.32
21.27 4.18 9.43
21.96 4.05 7.50
22.94 3.88 8.01
23.29 3.82 10.51
23.76 3.74 4.36
25.38 3.51 1.00
25.97 3.43 2.03
26.63 3.35 1.82
27.46 3.25 1.51
29.75 3.00 0.41
实施例9
一种AHU-377和缬沙坦三钠盐共结晶水合物晶型II的制备方法，包括以下步骤：
步骤1：称取221.3gAHU-377和225.2g缬沙坦，用3L甲苯搅拌分散于10L反应瓶中；称取62g氢氧化钠溶于1.5L乙醇配成溶液，将该氢氧化钠的乙醇溶液滴加到上述反应瓶中，反应得到溶液(投料摩尔比AHU-377∶缬沙坦∶氢氧化钠＝1.04∶1∶3)。对该溶液进行预过滤，确保去除其中可能存在的不溶杂质。将滤液转移到20L夹套反应釜，并补加10L甲苯稀释。
步骤2：将步骤1所得澄清溶液在50℃减压浓缩，当剩余体积在7L左右时停止浓缩，补加3L甲苯至总溶液体积10L左右，降至室温(～20℃)；
步骤3a：称取50g晶型II的晶种(添加量是目标产物的10％)，在500mL甲苯中超声1min分散后，加入到步骤2的溶液中，搅拌使晶种分散形成晶种床；
步骤3b：将32g水与5L乙酸乙酯混合均匀后，匀速加入上述晶种床中，时间为1h，滴加完毕后，体系维持搅拌熟化3h，过滤并用2L乙酸乙酯淋洗湿品，在30℃下真空干燥，得到目标产品晶型II。
对按照本发明方法和条件所得的其中7个批次的晶型II进行了XRPD和TGA测试，结果表明，均获得的是晶型II，且失重从小到大依次排序如下：5.60％；6.18％；6.68％；6.68％；8.06％；9.48％；9.68％。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范 围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (20)

  1. 一种AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，其特征在于，所述晶型II的X射线粉末衍射图(CuKα辐射)在2theta值为4.3°±0.2°、5.0°±0.2°、12.8°±0.2°处具有特征峰，所述制备方法包括以下步骤：
    步骤1：制备含有AHU-377和缬沙坦三钠盐复合物的澄清溶液，其中所述澄清溶液的溶剂包含第一溶剂和第二溶剂，所述第一溶剂是目标产物晶型II的反溶剂且能够与水共沸，所述第二溶剂是目标产物晶型II的正溶剂，且所述第二溶剂的沸点低于所述第一溶剂；
    步骤2：将步骤1所得澄清溶液在密闭条件下减压蒸发或氮气吹扫蒸发，以除去体系中的第二溶剂和水；以及，
    步骤3：将经过步骤2的体系与水、第三溶剂和选择性地晶型II的晶种混合，搅拌析晶，过滤，洗涤，干燥即得所述晶型II，所述第三溶剂为能够与第一溶剂互溶、且能与水混溶，且是目标产物晶型II的反溶剂。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤3的实施方式为：向经过步骤2的体系中加入所述晶型II的晶种，并搅拌使晶种分散形成晶种床，另将水与第三溶剂混合后，加入所述晶种床中，搅拌析晶，过滤，洗涤，干燥即得目标产物晶型II。
  3. 根据权利要求1或2所述的制备方法，其特征在于：步骤3中，晶种的投加量为目标晶型II理论产量的5wt％～15wt％。
  4. 根据权利要求3所述的制备方法，其特征在于：步骤3中，晶种的投加量为目标晶型II理论产量的8wt％～12wt％。
  5. 根据权利要求1或2所述的制备方法，其特征在于：步骤3中，先将晶种在所述第一溶剂中超声分散后，再加入经过步骤2的体系中。
  6. 根据权利要求2所述的制备方法，其特征在于：将水和第三溶剂的混合物 匀速加入到所述晶种床，加毕，维持搅拌熟化2～4h。
  7. 根据权利要求1所述的制备方法，其特征在于，步骤3的实施方式为：向经过步骤2的体系中加入水、第三溶剂，搅拌析晶，过滤，洗涤，干燥即得目标产物晶型II。
  8. 根据权利要求1或2或7所述的制备方法，其特征在于，步骤3中，所述搅拌析晶时间为2～4h。
  9. 根据权利要求1或2或7所述的制备方法，其特征在于：步骤3中，水与第三溶剂的体积比为1∶100～200。
  10. 根据权利要求1所述的制备方法，其特征在于：所述第一溶剂为甲苯、二甲苯、环己烷、乙酸异丙酯、甲基异丁基酮中的一种或多种的组合。
  11. 根据权利要求1或10所述的制备方法，其特征在于：所述第二溶剂为甲醇或乙醇或二者的组合。
  12. 根据权利要求1或10所述的制备方法，其特征在于：所述第三溶剂为选自乙酸乙酯、丙酮、2-丁酮、乙酸异丙酯以及甲基异丁基酮中的一种或多种的组合。
  13. 根据权利要求1或2或7所述的制备方法，其特征在于：步骤1中，先将AHU-377和缬沙坦用所述第一溶剂分散均匀得到分散液，将氢氧化钠加入到所述第二溶剂中获得氢氧化钠溶液，然后将所述分散液与氢氧化钠溶液混合，获得所述澄清溶液，其中AHU-377、缬沙坦以及氢氧化钠三者的投料摩尔比为1∶1.00～1.05∶2.95～3.05；或者，将AHU-377和缬沙坦三钠盐复合物溶解于所述第一溶剂和第二溶剂组成的混合溶剂中，即得所述澄清溶液。
  14. 根据权利要求1或2或7所述的制备方法，其特征在于：步骤1中，先将AHU-377和缬沙坦用所述第一溶剂分散均匀得到分散液，将氢氧化钠加入到 所述第二溶剂中获得氢氧化钠溶液，然后将所述分散液与氢氧化钠溶液混合，获得所述澄清溶液，其中AHU-377、缬沙坦以及氢氧化钠三者的投料摩尔比为1∶0.95～1∶2.95～3。
  15. 根据权利要求1或2或7所述的制备方法，其特征在于：步骤2中，控制所述减压蒸发的温度不超过50℃。
  16. 根据权利要求1或2或7所述的制备方法，其特征在于：步骤2中，蒸发至体系中第二溶剂和水的含量均低于0.1wt％时停止。
  17. 根据权利要求1或2或7所述的制备方法，其特征在于：在步骤2之后、步骤3之前，向体系内补加第一溶剂。
  18. 根据权利要求1所述的AHU-377和缬沙坦三钠盐共晶水合物晶型II的制备方法，其特征在于，步骤3中，将水与第三溶剂混合后，将混合物加入到经过步骤2的体系中搅拌析晶，或者，向经过步骤2的体系中加入晶种，然后加入水与第三溶剂的混合物。
  19. 根据权利要求1所述的制备方法，其特征在于：所述晶型II的X射线粉末衍射图(CuKα辐射)还在2theta值10.9°±0.2°处具有特征峰。
  20. 根据权利要求1或19所述的制备方法，其特征在于：所述晶型II的X射线粉末衍射图(CuKα辐射)还在2theta值5.8°±0.2°、5.5°±0.2°、18.9°±0.2°、14.6°±0.2°、18.5°±0.2°及20.1°±0.2°中的一处或多处具有特征峰。
PCT/CN2016/105335 2015-12-08 2016-11-10 一种ahu-377和缬沙坦三钠盐共晶水合物晶型ii的制备方法 WO2017097085A1 (zh)

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MX2018006969A MX2018006969A (es) 2015-12-08 2016-11-10 Método de preparación de la forma ii hidrato del cocristal de valasartán y ahu-377 trisódico.
KR1020187019105A KR102070392B1 (ko) 2015-12-08 2016-11-10 Ahu-377과 발사르탄 삼나트륨염의 공정 수화물의 결정형 ⅱ의 제조방법
EP16872277.5A EP3385256B1 (en) 2015-12-08 2016-11-10 Preparation method for eutectic hydrate crystal form ii of ahu-377 and diovan trisodium salt
PL16872277T PL3385256T3 (pl) 2015-12-08 2016-11-10 Sposób wytwarzania postaci ii krystalicznej eutektycznego hydratu ahu-377 i trisodowej soli diovanu
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CA3007864A CA3007864C (en) 2015-12-08 2016-11-10 Preparation method of trisodium ahu-377 and valsartan co-crystal hydrate form ii
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