WO2019052133A1 - Gsk1278863的晶型及其制备方法和制药用途 - Google Patents

Gsk1278863的晶型及其制备方法和制药用途 Download PDF

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WO2019052133A1
WO2019052133A1 PCT/CN2018/078766 CN2018078766W WO2019052133A1 WO 2019052133 A1 WO2019052133 A1 WO 2019052133A1 CN 2018078766 W CN2018078766 W CN 2018078766W WO 2019052133 A1 WO2019052133 A1 WO 2019052133A1
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solvent
crystalline form
gsk1278863
preparation
crystal form
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PCT/CN2018/078766
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English (en)
French (fr)
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陈敏华
张炎锋
王金秋
张晓宇
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苏州科睿思制药有限公司
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Priority to AU2018330994A priority Critical patent/AU2018330994A1/en
Priority to EP18857375.2A priority patent/EP3682884B1/en
Priority to ES18857375T priority patent/ES2980121T3/es
Priority to JP2020515707A priority patent/JP2020533396A/ja
Priority to CN201880059669.4A priority patent/CN111093668A/zh
Priority to CA3112277A priority patent/CA3112277A1/en
Publication of WO2019052133A1 publication Critical patent/WO2019052133A1/zh
Priority to US16/818,368 priority patent/US11117871B2/en
Priority to US17/174,006 priority patent/US11649217B2/en
Priority to US18/300,501 priority patent/US20230271927A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of a hypoxia-inducible factor prolyl hydroxylase inhibitor, a preparation method thereof and use thereof.
  • GSK1278863 (Daprodustat) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed by GlaxoSmithKline for the treatment of related anemia, such as anemia associated with chronic kidney disease.
  • GSK1278863 is a small molecule oral hypoxia-inducible factor prolyl hydroxylase inhibitor that inhibits prolyl hydroxylase and promotes the production of red blood cells, while red blood cells can carry oxygen to the body's required parts, thereby alleviating anemia. Purpose, which is similar to the effect that occurs in people at high altitudes.
  • GSK1278863 showed good anti-anemia effect and safety, and the effect was comparable to that of recombinant human erythropoietin for injection, and the safety was higher.
  • the oral dosage form of GSK1278863 is more convenient for patients than the injection method of macromolecular recombinant human erythropoietin.
  • GSK1278863 N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine (hereinafter referred to as "compound (I)”)),
  • the structure is as follows:
  • Patent CN101505752B discloses the chemical structure and preparation method of GSK1278863. The inventors repeated the preparation method to obtain a solid of GSK1278863, which has low purity, high impurity content and high hygroscopicity, and is not suitable for medicinal use. The inventors have found crystal forms CS1 and CS9 of GSK1278863 which are excellent in performance. The crystalline forms CS1 and CS9 of the GSK1278863 of the present invention are higher in purity and lower in hygroscopicity than the existing solids.
  • novel crystal form provided by the invention has good stability, is not easy to be degraded, has good solubility, good fluidity and has an ideal in vitro dissolution in the preparation, and provides a better choice for the preparation of a pharmaceutical preparation containing GSK1278863 for drug development. Very important.
  • the main object of the present invention is to provide a crystal form of GSK1278863, a preparation method thereof and use thereof.
  • the present invention provides the crystal form CS1 of the compound (I) (hereinafter referred to as "crystal form CS1").
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 7.5° ⁇ 0.2°, and 7.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has one or more of the diffraction angle 2 ⁇ values of 17.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 17.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 7.5° ⁇ 0.2°, 7.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 21.0°. There are characteristic peaks at ⁇ 0.2°, 24.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS1 is as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS1, characterized in that the method comprises:
  • the cyclic ether solvent in the method (1) is preferably tetrahydrofuran;
  • the ketone solvent is preferably one of acetone, methyl isobutyl ketone or any mixture thereof; and
  • the volatilization temperature is preferably room temperature. Or 50 °C.
  • the cyclic ether solvent in the method (2) is preferably 1,4-dioxane; the anti-solvent is preferably water; the crystallization time is 0.5 to 24 hours;
  • the crystallization time in the method (2) is preferably 2 hours.
  • the present invention also provides the crystal form CS9 of the compound (I) (hereinafter referred to as "crystal form CS9").
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ of 4.6° ⁇ 0.2°, 6.6° ⁇ 0.2°, 21.1° ⁇ 0.2°, 9.4° ⁇ 0.2°, 20.2°. There are characteristic peaks at ⁇ 0.2° and 24.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS9 is as shown in FIG.
  • the ether solvent in the method (1) is preferably methyl tert-butyl ether;
  • the high polymer is preferably composed of equal mass of polycaprolactone, polyoxyethylene, polymethyl methacrylate, hydroxy a polymer composed of ethyl cellulose and sodium alginate;
  • the volatilization temperature is preferably 50 °C.
  • the ester solvent in the method (2) is preferably ethyl acetate; the alcohol solvent is preferably ethanol; and the volume ratio of the ester solvent to the alcohol solvent is 1:10 to 10:1;
  • the volatilization temperature is preferably 50 ° C;
  • volume ratio of the ester solvent to the alcohol solvent in the method (2) is preferably 1:1.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the GSK1278863 as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) as a raw material is in the form of a solid powder.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • 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. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • 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.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline forms CS1 and CS9 of the present invention are pure, unitary, and are substantially free of any other crystalline 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 Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the crystal form provided by the present invention is higher in purity than the prior art.
  • the existing solid has a purity of 81.06% and a high impurity content.
  • the present invention provides a crystal form purity greater than 99%, and in another specific embodiment, the present invention provides a crystal form having a purity greater than 99.5%;
  • the crystalline form CS1 and the crystalline form CS9 of the present invention have good stability.
  • the crystalline form CS1 and the crystalline form CS9 of the present invention are openly placed at 25 ° C / 60% relative humidity, accelerated conditions of 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, and the crystal form remains unchanged for at least 3 months.
  • the purity of the invention remains substantially unchanged during the standing process; after the crystalline forms CS1 and CS9 of the present invention are mixed with the auxiliary materials to form a pharmaceutical preparation, the crystal of the present invention is prepared in the preparation after being allowed to stand under accelerated conditions of 40 ° C / 75% relative humidity for 1 month.
  • the type remains the same.
  • the crystal form provided by the invention has good stability, thereby ensuring consistent and controllable quality of the sample, and is important for ensuring the efficacy and safety of the drug, avoiding toxicity caused by impurities, and preventing the occurrence of adverse drug reactions;
  • the crystal form provided by the invention has good solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystal form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the human body, and achieves an ideal medicine. Bioavailability and efficacy;
  • the crystal form of the present invention has a good dissolution rate and a faster dissolution rate after being made into a pharmaceutical tablet.
  • the average dissolution rate at 10 minutes reached 67.7%, and the average dissolution rate at 60 minutes reached 95.2%.
  • Good in vitro dissolution is beneficial to improve the absorption of the drug, to ensure better in vivo exposure characteristics, thereby improving bioavailability and making the drug more effective; the faster in vitro dissolution rate allows the drug to reach the highest in plasma quickly after administration.
  • the concentration value which in turn ensures the rapid onset of the drug and improves the efficacy.
  • crystalline form CS1 or the crystalline form CS9 provided by the present invention or any mixture thereof in the preparation of a medicament containing a hypoxia-inducible factor prolyl hydroxylase inhibitor.
  • Figure 1 is an XRPD pattern of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Fig. 2 is a 1 H NMR chart of the crystal form CS1 obtained in Example 1 according to the present invention.
  • Figure 3 is a DSC chart of a crystalline form CS1 obtained according to Example 1 of the present invention.
  • Example 4 is a TGA diagram of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Figure 5 is an XRPD pattern of a crystal form CS1 obtained according to Example 2 of the present invention.
  • Figure 6 is an XRPD pattern of a crystalline form CS9 obtained according to Example 5 of the present invention.
  • Figure 7 is a 1 H NMR spectrum of the crystalline form CS9 obtained according to Example 5 of the present invention.
  • Figure 8 is a DSC diagram of a crystalline form CS9 of the present invention.
  • Figure 9 is a TGA diagram of the crystalline form CS9 of the present invention.
  • Figure 10 is a DVS diagram of the crystal form CS1 of the present invention.
  • Figure 11 is a DVS diagram of a crystalline form CS9 of the present invention.
  • Figure 12 is a DVS diagram of a conventional solid.
  • Figure 13 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 25 ° C / 60% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • Figure 14 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 40 ° C / 75% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • Figure 15 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 60 ° C / 75% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • Figure 16 is an XRPD overlay of the crystalline form CS9 of the present invention placed at 25 ° C / 60% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • Figure 17 is an XRPD overlay of the crystalline form CS9 of the present invention placed at 40 ° C / 75% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • Figure 18 is an XRPD overlay of the crystalline form CS9 of the present invention placed at 60 ° C / 75% relative humidity for 3 months (the top view is before placement and the lower figure is after placement).
  • 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
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • 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:
  • H NMR data (1 HNMR) collected from BrukerAvance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide (DMSO) to prepare a solution of 2-10 mg/mL.
  • DMSO deuterated dimethyl sulfoxide
  • HPLC high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • the GSK1278863 starting material used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in CN101505752B.
  • the prior art solids in the following examples refer to the solids of GSK1278863 obtained by the present inventors by the preparation method disclosed in CN101505752B.
  • the nuclear magnetic resonance spectrum is shown in Fig. 2.
  • the DSC curve of the crystalline form CS1 obtained in this example is shown in Fig. 3.
  • an endothermic peak appears, which is the melting endothermic peak of the crystalline form CS1.
  • the TGA curve of the crystal form CS1 obtained in this example is as shown in Fig. 4, and when heated to around 150 ° C, it has a mass loss of about 0.6%.
  • Example 2 A certain mass of GSK1278863 raw material was weighed, dissolved in a solvent as shown in Table 2 below, and then volatilized at 50 ° C to obtain a solid.
  • the solids obtained in Example 2 and Example 3 were respectively labeled as Sample 2 and Sample 3.
  • the solids obtained in Sample 2 and Sample 3 were all tested for Form CS1.
  • Sample 2 was selected for test characterization, and its X-ray powder diffraction data is shown in Figure 5 and Table 3.
  • the nuclear magnetic resonance spectrum is shown in Fig. 7.
  • GSK 1278863 raw material was weighed and dissolved in 0.7 mL of a mixed solvent of ethyl acetate and ethanol in a volume ratio of 1:1, and the solid was precipitated at 50 ° C for about 4 days, and the obtained solid was a crystalline form of CS9.
  • the DSC curve of the crystalline form CS9 of the present invention is as shown in Fig. 8. When heated to around 145 ° C, an endothermic signal begins to appear, and when heated to around 237 ° C, an endothermic peak begins to appear.
  • the TGA curve of the crystal form CS9 of the present invention is as shown in Fig. 9, and when heated to around 150 ° C, it has a mass loss gradient of about 0.2%.
  • Example 7 Comparison of hygroscopicity between crystalline form CS1, crystalline form CS9 and existing solids of the present invention
  • the hygroscopicity of the crystalline forms CS1, CS9 of the present invention and about 10 mg of the existing solids were measured by dynamic moisture adsorption (DVS) at 25 ° C.
  • the experimental results are shown in Table 5.
  • the DVS patterns of the crystal forms CS1, CS9 and the existing solids are shown in Figures 10, 11 and 12, respectively.
  • Example 8 Comparison of purity of crystalline form CS1, crystalline form CS9 and existing solid of the present invention
  • the crystal form of the invention has high purity, meets the stringent requirements on the purity of the raw material in the preparation, and is suitable for subsequent preparation of the preparation and production of the medicine.
  • Example 9 Study on the stability of the crystalline form CS1 of the present invention
  • the crystal form CS1 of the present invention is placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, respectively, and the XRPD overlays before and after placement are as shown in Fig. 13 and Fig. 14 respectively. As shown in Fig. 15, the results are shown in Table 7.
  • the inventors also studied the purity change of the crystalline form CS1 before and after being exposed for 30 months at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, and the results are shown in the table. 8 is shown.
  • the crystalline form CS1 of the present invention has a crystal form which remains unchanged for at least 3 months at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, and has good physical stability.
  • the purity remains basically unchanged during the placement process, is not easy to degrade, and has good chemical stability.
  • the crystal form CS1 has good physical stability, and ensures that the raw materials are not easily converted into other crystal forms during storage and preparation processes, thereby ensuring consistent and controllable sample quality.
  • the crystalline form CS1 has good chemical stability, and the purity is basically unchanged during storage, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the stable crystal form is more controllable during the crystallization process, and impurities and mixed crystals are less likely to occur, which is advantageous for industrial production.
  • the stability after preparation into a pharmaceutical preparation can be expected to provide a guarantee for the preparation of a stable preparation.
  • Example 10 Study on the stability of the crystalline form CS9 of the present invention
  • the inventors also studied the purity change of the crystalline form CS9 before and after being placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity for one month. 10 is shown.
  • the crystalline form CS9 of the present invention has a crystal form which remains unchanged for at least 3 months at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity, and the purity is placed for 1 month.
  • the process remains basically unchanged, indicating that the crystalline form CS9 has good stability, is not easy to be converted into other crystal forms, and is not easy to be degraded, thereby providing a guarantee for preparing a stable preparation.
  • Example 11 Dynamic solubility of crystalline form CS1 and crystalline form CS9
  • the present invention provides a solvent system of four pH values of 1.2 to 7.5. Specifically, SGF (simulated gastric juice) having a pH of 1.8, FeSSIF (simulated artificial intestinal juice in a fed state) having a pH of 5.0, FaSSIF having a pH of 6.5 (simulated artificial intestinal juice in a fasting state), and pure water.
  • SGF simulated gastric juice
  • FeSSIF simulated artificial intestinal juice in a fed state
  • FaSSIF having a pH of 6.5
  • pure water pure water
  • Solubility is one of the key properties of drugs, directly affecting the absorption of drugs in the human body.
  • the solubility of different crystal forms may be significantly different, and the absorption dynamics in the body may also change, resulting in differences in bioavailability, which ultimately affects the clinical safety and efficacy of the drug.
  • Compound (I) is a poorly soluble drug, and for poorly soluble drugs, it is more important to increase solubility. Increased solubility will help improve the bioavailability of the drug, thereby increasing the drug's drug properties. In addition, the increase in solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystal form CS1 and the crystal form CS9 of the invention have good solubility in SGF, FeSSIF, FaSSIF and pure water, which provides a good solution for the good dissolution of the crystal form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, and is ideal. Drug bioavailability and efficacy.
  • Crystal form Bulk density (g/ml) Tap density (g/ml) Compressibility coefficient (%) fluidity CS1 0.15 0.19 twenty one Acceptable CS9 0.11 0.14 twenty one general
  • Liquidity evaluation criteria (refer to US Pharmacopoeia 1174): compressibility coefficient ⁇ 10%, excellent fluidity; 11% to 15%, good fluidity; 16% to 20%, general mobility; 21% to 25% , fluidity is acceptable; 26% to 31%, poor liquidity; 32% to 37%, poor liquidity; >38%, extremely poor liquidity.
  • Example 13 Study on the preparation of crystalline form CS1 and crystalline form CS9
  • the obtained tablets were tested for dissolution in vitro, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions, as follows:
  • the dissolution of the crystalline form CS1 is shown in Table 15 below, and as shown in Fig. 19, the results show that the above-mentioned tablet having the crystalline form CS1 of the present invention as an active ingredient has an average dissolution rate of 67.7% at 10 minutes and an average dissolution rate at 60 minutes. It reached 95.2% with good dissolution and faster dissolution rate.
  • the crystalline form CS1 and the crystalline form CS9 of the invention have good stability in the preparation, and ensure that they are not easily converted into other crystal forms during the preparation process and the storage process of the preparation, thereby ensuring consistent and controllable quality of the medicine.

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Abstract

一种缺氧诱导因子脯氨酰羟化酶抑制剂化合物（I）GSK1278863的晶型CS1和CS9，及其制备方法和其在制备用于治疗和/或预防贫血的药物制剂中的用途。

Description

[根据细则37.2由ISA制定的发明名称]　GSK1278863的晶型及其制备方法和制药用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及一种缺氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法和用途。
背景技术
GSK1278863(Daprodustat)是一种口服缺氧诱导因子脯氨酰羟化酶抑制剂，由葛兰素史克研发，用于治疗相关贫血，如慢性肾脏病相关的贫血。
目前，治疗慢性肾脏病相关贫血的标准疗法为注射重组人促红细胞生成素。而注射大分子重组人促红细胞生成素常伴有心血管方面的安全性问题。GSK1278863是一种小分子口服缺氧诱导因子脯氨酰羟化酶抑制剂，能抑制脯氨酰羟化酶从而促进红细胞的产生，而红细胞可携带氧至机体需要的部位，从而达到缓解贫血的目的，这与人在高海拔地区时机体内发生的效应相似。临床中GSK1278863表现出良好的缓解贫血的效果和安全性，效果与注射用重组人促红细胞生成素相当，且安全性更高。此外，GSK1278863的口服剂型与大分子重组人促红细胞生成素的注射方式相比，病人服用更为方便。
GSK1278863的化学名称为：N-[(1,3-二环己基六氢-2,4,6-三氧代-5-嘧啶基)羰基]甘氨酸(以下称“化合物(I)”)，其结构式如下所示：
Figure PCTCN2018078766-appb-000001
在药物研究领域，不同的药物晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、机械稳定性等，这些特性可以影响药物制剂的质量、安全性和有效性，从而导致临床药效差异。因此，晶型研究和控制成为药物研发过程中的重要研究内容。
至今，无GSK1278863的晶型信息公开。专利CN101505752B公开了GSK1278863的化学结构和制备方法，本发明人重复该制备方法得到GSK1278863的固体，该固体纯度低，杂质含量极高且吸湿性较高，不适合药用。本发明人发现了性能优异的GSK1278863的晶型CS1和CS9。相比现有固体，本发明GSK1278863的晶型CS1和CS9纯度高，且吸湿性更低。此外，本发明 提供的新晶型稳定性好、不易降解、溶解度良好、流动性好且在制剂中具有理想的体外溶出，为含GSK1278863的药物制剂的制备提供了更好的选择，对于药物开发具有非常重要的意义。
发明内容
本发明的主要目的是提供GSK1278863的晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的晶型CS1(以下称作“晶型CS1”)。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、7.5°±0.2°、7.9°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为17.2°±0.2°、21.0°±0.2°、24.0°±0.2°、19.3°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为17.2°±0.2°、21.0°±0.2°、24.0°±0.2°、19.3°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、7.5°±0.2°、7.9°±0.2°、17.2°±0.2°、21.0°±0.2°、24.0°±0.2°、19.3°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如附图1所示。
根据本发明的目的，本发明还提供晶型CS1的制备方法，其特征在于，所述方法包括：
(1)将GSK1278863溶解在环醚类溶剂或酮类溶剂中，在10～50℃下挥发析晶获得；或
(2)将GSK1278863溶解在环醚类溶剂中，添加反溶剂析晶，后分离、干燥而获得；
进一步的，方法(1)中所述环醚类溶剂优选为四氢呋喃；所述酮类溶剂优选为丙酮、甲基异丁基酮中的一种或它们的任意混合；所述挥发温度优选为室温或50℃。
进一步的，方法(1)中所述酮类溶剂更优选为丙酮或甲基异丁基酮。
进一步的，方法(2)中所述环醚类溶剂优选为1,4-二氧六环；所述反溶剂优选为水；所述析晶时间为0.5～24小时；
进一步的，方法(2)中所述析晶时间优选为2小时。
根据本发明的目的，本发明还提供化合物(I)的晶型CS9(以下称作“晶型CS9”)。
使用Cu-Kα辐射，所述晶型CS9的X射线粉末衍射在衍射角2θ值为4.6°±0.2°、6.6°±0.2°、21.1°±0.2°处有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为9.4°±0.2°、20.2°±0.2°、24.2°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为9.4°±0.2°、20.2°±0.2°、24.2°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为4.6°±0.2°、6.6°±0.2°、21.1°±0.2°、9.4°±0.2°、20.2°±0.2°、24.2°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS9的X射线粉末衍射谱图如附图6所示。
根据本发明的目的，本发明还提供晶型CS9的制备方法，其特征在于，所述方法包括：
(1)将GSK1278863溶解在醚类溶剂中，并加入高聚物，于10～70℃下挥发析晶而获得；或
(2)将GSK1278863溶解在酯类和醇类溶剂的混合体系中，于10～70℃下挥发析晶而获得；
进一步的，方法(1)中所述醚类溶剂优选为甲基叔丁基醚；所述高聚物优选为由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成的高聚物；所述挥发温度优选为50℃。
进一步的，方法(2)中所述酯类溶剂优选为乙酸乙酯；所述醇类溶剂优选为乙醇；所述酯类溶剂和醇类溶剂的体积比为1:10～10:1；所述挥发温度优选为50℃；
更进一步的，方法(2)中所述酯类溶剂和醇类溶剂的体积比优选为1:1。
在本发明的晶型CS1和CS9的制备方法中：
所述“室温”不是精确的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述GSK1278863指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物(I)为固体粉末形式。
本发明中，“晶体”或“多晶型”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。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。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，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。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。
在一些实施方案中，本发明的晶型CS1和CS9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。
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。
本发明提供的晶型具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型吸湿性更低。现有固体在80％相对湿度的增重量为1.14％，而本发明晶型CS1和晶型CS9在80％相对湿度的增重量分别为0.53％和0.22％，几乎不吸水增重，在高湿度条件下非常稳定，更有利于原料药长期存储和制剂的制备；
(2)与现有技术相比，本发明提供的晶型纯度更高。现有固体纯度为81.06％，杂质含量很高。在具体的实施例中，本发明提供的晶型纯度大于99％，在另一个具体的实施例中，本发明提供的晶型的纯度大于99.5％；
(3)本发明晶型CS1和晶型CS9具有良好的稳定性。本发明晶型CS1和晶型CS9在25℃/60％相对湿度、加速条件40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，至少3个月晶型保持不变，且放置过程中纯度基本保持不变；本发明的晶型CS1和CS9与辅料混合做成药物制剂后，在加速条件40℃/75％相对湿度下放置1个月后，制剂中本发明的晶型保持不变。本发明提供的晶型稳定性好，从而保证样品的质量一致可控，对保证药物疗效和安全性，避免杂质产生的毒性，防止药物不良反应的发生具有重要意义；
(4)本发明提供的晶型在模拟生物介质和纯水中具有良好的溶解度，为制剂中晶型的良好溶出提供保障，有利于制剂中活性成分在人体内的有效吸收，达到理想的药物生物利用度和药效；
(5)本发明晶型做成药物片剂后还具有良好的溶出度和较快的溶出速率。在pH＝6.8磷酸盐缓冲溶液介质中，10分钟时的平均溶出度达到67.7％，60分钟时的平均溶出度达95.2％。良好的体外溶出利于提高药物吸收程度，保证更好的体内暴露特性，从而提高生物利用度，使得药物的疗效更好；较快的体外溶出速率使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效并提高药效。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明的晶型CS1或晶型CS9或它们的任意混合，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提供的晶型CS1或晶型CS9或它们的任意混合在制备含缺氧诱导因子脯氨酰羟化酶抑制剂的药物中的用途。
更进一步地，本发明提供的晶型CS1或晶型CS9或它们的任意混合在制备治疗和/或预防贫血的药物中的用途。
附图说明
图1为根据本发明实施例1所得晶型CS1的XRPD图。
图2为根据本发明实施例1所得晶型CS1的 1HNMR谱图。
图3为根据本发明实施例1所得晶型CS1的DSC图。
图4为根据本发明实施例1所得晶型CS1的TGA图。
图5为根据本发明实施例2所得晶型CS1的XRPD图。
图6为根据本发明实施例5所得晶型CS9的XRPD图。
图7为根据本发明实施例5所得晶型CS9的 1HNMR谱图。
图8为本发明晶型CS9的DSC图。
图9为本发明晶型CS9的TGA图。
图10为本发明晶型CS1的DVS图。
图11为本发明晶型CS9的DVS图。
图12为现有固体的DVS图。
图13为本发明晶型CS1在25℃/60％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图14为本发明晶型CS1在40℃/75％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图15为本发明晶型CS1在60℃/75％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图16为本发明晶型CS9在25℃/60％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图17为本发明晶型CS9在40℃/75％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图18为本发明晶型CS9在60℃/75％相对湿度下放置3个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图19为含本发明晶型CS1的片剂在pH＝6.8磷酸盐缓冲溶液中的溶出曲线。
具体实施方式
本发明进一步参考以下实施例限定，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。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1HNMR：液态核磁氢谱
DMSO：二甲亚砜
采集数据所用的仪器及方法：
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射线光源：Cu,Kα
Kα1
Figure PCTCN2018078766-appb-000002
：1.540598；Kα2
Figure PCTCN2018078766-appb-000003
：1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：如无特别说明为10℃/min
保护气体：N 2
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：N 2
核磁共振氢谱数据( 1HNMR)采自于BrukerAvance II DMX 400M HZ核磁共振波谱仪。 称量1-5mg样品，用0.5mL氘代二甲亚砜(DMSO)溶解，配成2-10mg/mL的溶液。
本发明用于纯度测试的高效液相色谱(HPLC)数据采集来自于安捷伦1260，所用检测器为紫外可变波长检测器(VWD)。本发明所述的HPLC方法参数如下：
色谱柱：Xbridge C8,150×4.6mm,3.5μm
流动相：A:0.1％ TFA 在水中
B:0.1％ TFA 在乙腈中
洗脱梯度：
时间(min) ％B
0.0 20
5.0 50
30.0 80
35.0 80
35.1 20
40.0 20
流速：1.0mL/min
进样量：3μL
柱温：40℃
稀释剂：MeOH
用于溶解度测试的高效液相色谱(HPLC)数据采集来自于安捷伦1260，所用检测器为紫外可变波长检测器(VWD)。本发明所述的HPLC方法参数如下：
色谱柱：Xbridge C8,150×4.6mm,5μm
流动相：A:0.1％ TFA 在水中
B:0.1％ TFA 在乙腈中
洗脱梯度：
时间(min) ％B
0.0 65
10.0 80
12.0 80
12.1 65
16.0 65
流速：1.1mL/min
进样量：5μL
柱温：40℃
稀释剂：MeOH
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用到的GSK1278863原料是根据现有技术制备得到，例如根据CN101505752B中公开的制备方法得到。以下实施例中现有技术固体是指本发明人重复CN101505752B公开的制备方法得到的GSK1278863的固体。
实施例1～4：制备晶型CS1
实施例1
称取6.4mg的GSK1278863原料，溶解于0.5mL四氢呋喃溶剂中，后于室温下挥发约2天析出固体，经检测，所得固体为晶型CS1，其X射线粉末衍射数据如图1，表1所示。
核磁共振氢谱谱图如图2所示，核磁数据为： 1HNMR(400MHz,d 6-DMSO)δ 10.18(s,1H),4.62(s,2H),4.11(d,J＝5.8Hz,2H),2.26(d,J＝10.9Hz,4H),1.78(d,J＝12.6Hz,4H),1.60(t,J＝11.8Hz,6H),1.27(d,J＝12.9Hz,4H),1.13(s,2H)。
本实施例所得晶型CS1的DSC曲线如图3所示，加热至242℃附近开始出现一个吸热峰，该吸热峰为晶型CS1的熔化吸热峰。
本实施例所得晶型CS1的TGA曲线如图4所示，加热至150℃附近时，具有约0.6％的质量损失。
表1
衍射角2θ d值 强度％
3.94 22.44 7.43
5.53 15.98 3.05
6.41 13.80 41.18
7.51 11.77 100.00
7.94 11.14 52.84
10.16 8.71 1.90
12.80 6.91 2.00
13.47 6.57 2.08
15.20 5.83 5.68
15.89 5.58 2.92
17.15 5.17 15.13
18.52 4.79 3.88
19.25 4.61 13.52
19.92 4.46 7.60
20.41 4.35 11.08
20.99 4.23 24.54
22.60 3.93 2.29
24.04 3.70 10.32
26.08 3.42 2.46
27.19 3.28 2.23
32.89 2.72 0.61
实施例2～3：
称取一定质量的GSK1278863原料，溶解至如下表2中所示的溶剂中，后于50℃下挥发得到固体，实施例2和实施例3所得固体分别标记为样品2和样品3。经检测，样品2和样品3所得固体均为晶型CS1。选取样品2进行测试表征，其X射线粉末衍射数据如图5，表3所示。
表2
实施例 原料质量(mg) 溶剂 溶剂体积(mL) 样品标记
2 6.7 甲基异丁基酮 0.7 2
3 6.6 丙酮 0.7 3
表3
衍射角2θ d值 强度％
3.93 22.47 5.30
6.35 13.93 37.90
7.53 11.75 100.00
7.92 11.17 41.23
10.12 8.74 1.65
12.80 6.92 2.37
13.44 6.59 2.83
15.19 5.83 6.22
15.92 5.57 0.81
17.13 5.18 8.90
18.60 4.77 1.07
19.27 4.61 14.44
19.75 4.50 7.17
20.00 4.44 5.18
20.41 4.35 5.27
21.00 4.23 28.87
22.64 3.93 1.35
24.02 3.71 7.91
25.04 3.56 1.66
26.11 3.41 2.34
27.24 3.27 1.55
28.18 3.17 0.69
28.83 3.10 0.58
32.76 2.73 0.86
36.60 2.46 0.50
实施例4：
称取10.1mg的GSK1278863原料溶解于0.5mL 1,4-二氧六环溶剂中，逐滴加入2.0mL的反溶剂水，室温下搅拌2小时，离心，真空干燥得到结晶固体。经检测，所得结晶固体为晶型CS1。
实施例5～6：制备晶型CS9
实施例5：
称取4.6mg GSK 1278863原料加入到0.7mL的甲基叔丁基醚溶剂中，加入由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成的高聚物，50℃下挥发约1天析出固体。经检测，所得固体为晶型CS9，其X射线粉末衍射数据如图6、表4所示。
核磁共振氢谱谱图如图7所示，核磁数据为： 1HNMR(400MHz,d 6-DMSO)δ 10.18(s,1H),4.62(s,2H),4.10(d,J＝5.6Hz,2H),2.36–2.17(m,4H),1.78(d,J＝12.4Hz,4H),1.60(s,6H),1.34–1.21(m,4H),1.11(d,J＝13.1Hz,2H)。
表4
衍射角2θ d值 强度％
4.58 19.29 19.65
6.56 13.47 100.00
9.37 9.44 13.93
10.50 8.43 4.37
13.34 6.64 2.86
15.10 5.87 1.57
17.13 5.18 4.23
18.51 4.79 1.99
19.54 4.54 4.14
20.18 4.40 17.65
21.14 4.20 15.46
24.23 3.67 7.74
30.20 2.96 0.63
实施例6：
称取约6.9mg GSK 1278863原料溶于0.7mL体积比为1:1的乙酸乙酯和乙醇的混合溶剂中，50℃下挥发约4天析出固体，经检测，所得固体为晶型CS9。
本发明晶型CS9的DSC曲线如图8所示，加热至145℃附近时，开始出现一个吸热信号，加热至237℃附近时，开始出现一个吸热峰。
本发明晶型CS9的TGA曲线如图9所示，加热至150℃附近时，具有约0.2％的质量损失梯度。
实施例7：本发明晶型CS1、晶型CS9和现有固体的吸湿性比较
在25℃条件下，取本发明的晶型CS1、CS9和现有固体各约10mg进行动态水分吸附(DVS)测试其吸湿性，实验结果如表5所示。晶型CS1、CS9和现有固体的DVS图分别如图10、图11和图12所示。
表5 吸湿性数据对比
形态 80％相对湿度的增重
晶型CS1 0.53％
晶型CS9 0.22％
现有固体 1.14％
结果表明，在25℃，80％相对湿度条件下，本发明晶型CS1和晶型CS9几乎不吸水增重，在高湿度条件下非常稳定，不易吸湿。相比之下，现有固体在相同条件下吸水增重量大，吸湿性较强。
低引湿性的晶型在制备过程中无需特殊的干燥条件，简化了药物的制备与后处理工艺，利于工业化生产。本发明的晶型CS1和晶型CS9相比现有固体具有更低的吸湿性，降低了存储环境的要求，例如在储存中不必刻意控制环境湿度，节约成本，更有利于原料药和制 剂的长期储存。
实施例8：本发明晶型CS1、晶型CS9和现有固体的纯度比较
采用HPLC测定本发明晶型CS1、晶型CS9和现有固体的纯度，结果如下表6所示。
表6
形态 晶型CS1 晶型CS9 现有固体
纯度 99.88％ 99.86％ 81.06％
杂质含量 0.12％ 0.14％ 18.94％
药物的纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。现有固体的杂质含量极高，高达18.94％，会使药物含量明显偏低或活性降低；杂质含量高也会使毒副作用显著增加，因此现有固体原料药不能直接用于制剂的制备。
本发明的晶型具有较高的纯度，满足制剂中对原料药纯度的苛刻要求，适合用于后续的制剂制备和药品生产。
实施例9：本发明晶型CS1稳定性研究
取本发明晶型CS1分别置于25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，放置前后的XRPD叠图分别如图13、图14和图15所示，结果如表7所示。
表7
Figure PCTCN2018078766-appb-000004
此外，本发明人还研究了晶型CS1在25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置3个月前后的纯度变化，结果如表8所示。
表8
Figure PCTCN2018078766-appb-000005
Figure PCTCN2018078766-appb-000006
本发明的晶型CS1在25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下，至少放置3个月晶型保持不变，具有良好的物理稳定性，且纯度在放置过程中基本保持不变，不易发生降解，具有良好的化学稳定性。
作为药物中最关键的活性成分，晶型具有良好的物理和化学稳定性至关重要。晶型CS1具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。
药物在存储过程中，纯度降低会使得药物含量明显偏低，活性降低，纯度降低还使得毒副作用显著增加，影响药物的疗效和安全性。晶型CS1具有良好的化学稳定性，储存过程中纯度基本不变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。此外，稳定的晶型在结晶工艺过程中更加可控，不容易出现杂质和混晶，利于工业化生产。
从晶型CS1的原料药稳定性结果可预期其制备成为药物制剂后的稳定性，为制备稳定的制剂提供保障。
实施例10：本发明晶型CS9稳定性研究
取本发明晶型CS9分别置于25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，放置前后的XRPD叠图分别如图16、图17和图18所示，结果如表9所示。
表9
Figure PCTCN2018078766-appb-000007
同时，本发明人还研究了晶型CS9在25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置1个月前后的纯度变化，结果如表10所示。
表10
Figure PCTCN2018078766-appb-000008
Figure PCTCN2018078766-appb-000009
本发明的晶型CS9在25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下，至少放置3个月晶型保持不变，且纯度在放置1个月过程中基本保持不变，说明晶型CS9具有良好的稳定性，不易转变为其它晶型，也不易发生降解，为制备稳定的制剂提供保障。
实施例11：晶型CS1和晶型CS9的动态溶解度
参照《中国药典》附录中溶解度测定法；结合生物体内不同器官部位的pH值变化。根据上述两种参考依据，本发明设置了1.2～7.5等4个pH值的溶媒系统。具体为：pH为1.8的SGF(模拟胃液)，pH为5.0的FeSSIF(模拟进食状态下人工肠液)，pH为6.5的FaSSIF(模拟空腹状态下人工肠液)以及纯水。
取本发明晶型CS1和晶型CS9，分别用SGF，FeSSIF，FaSSIF和纯水配制成饱和溶液，在固定的时间点取样并通过高效液相色谱(HPLC)法测定饱和溶液中晶型CS1和晶型CS9的动态溶解度，实验结果如表11和表12所示。
表11 晶型CS1的动态溶解度数据
Figure PCTCN2018078766-appb-000010
表12 晶型CS9的动态溶解度数据
Figure PCTCN2018078766-appb-000011
溶解度是药物的关键性质之一，直接影响药物在人体内的吸收。不同晶型药物的溶解度可能会存在明显差异，体内吸收动态也会发生变化，造成生物利用度的差异，最终影响到药物的临床安全性和疗效。
化合物(I)为难溶性药物，对难溶性药物而言，提高溶解度更为重要。溶解度的提高将有助于提高药物的生物利用度，从而提高药物的成药性。此外，溶解度升高能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
本发明晶型CS1和晶型CS9的在SGF，FeSSIF，FaSSIF和纯水中的溶解度良好，为制剂中晶型的良好溶出提供保障，有利于制剂中活性成分在人体内的有效吸收，达到理想的药物生物利用度和药效。
实施例12：晶型CS1和晶型CS9的流动性研究
按照美国药典(USP)1174，通过可压性系数对本发明的晶型CS1和CS9进行流动性评估。测定晶型CS1和CS9的堆密度和振实密度后，计算可压性系数，结果如表13所示。
1.测试方法：
样品：晶型CS1和晶型CS9
仪器：振实仪
器皿：5ml量筒
振动次数：500次
堆密度＝m/v 0(质量/振实前体积)
振实密度＝m/v t(质量/振实后体积)
2.计算公式：可压性系数(％)＝(振实密度–堆密度)/振实密度×100％
3.测试结果：
表13
晶型 堆密度(g/ml) 振实密度(g/ml) 可压性系数(％) 流动性
CS1 0.15 0.19 21 可接受
CS9 0.11 0.14 21 一般
*流动性评估标准(参考美国药典1174)：可压性系数≤10％，流动性极好；11％～15％，流动性好；16％～20％，流动性一般；21％～25％，流动性可接受；26％～31％，流动性差；32％～37％，流动性很差；>38％，流动性极差。
结果表明，本发明晶型CS1和晶型CS9的流动性符合制剂开发要求，能保证制剂的混合均匀度及含量均匀度、降低剂型的重量差异，保证产品质量，适合药用。
实施例13：晶型CS1和晶型CS9在制剂中的研究
1.GSK1278863片剂的制备：
称取GSK1278863的晶型CS1或晶型CS9、微晶纤维素、交联羧甲基纤维素钠和硬脂 酸镁(各组分含量如下表14所示)，混合2分钟。用手动压片机压制成片，直径7mm圆形冲模，压力5KN±1KN，片重100mg±1mg。用35cc HDPE瓶包装(每瓶一片)，每瓶含有1g干燥剂，用封口机封口。经检测，制剂制备前后，活性成分的晶型未发生变化。
表14
片剂成分 质量(mg/片) 质量比(％)
晶型CS1或晶型CS9 12.50 12.50
微晶纤维素 81.50 81.50
交联羧甲基纤维素钠 5.00 5.00
硬脂酸镁 1.00 1.00
合计 100 100
2.体外溶出测试：
对获得的片剂测试体外溶出情况，溶出度的测定按照中国药典2015年版0931溶出度与释放度测定法，条件如下：
溶出介质：pH＝6.8磷酸盐缓冲溶液+质量浓度为1％的十二烷基硫酸钠水溶液
溶出方法：桨法
介质体积：900mL
转速：75rpm
介质温度：37℃
晶型CS1的溶出情况如下表15，图19所示，结果表明上述以本发明晶型CS1为活性成分的片剂在10分钟时的平均溶出度达到67.7％，在60分钟时的平均溶出度达到95.2％，具有良好的溶出度和较快的溶出速率。
溶出是吸收的前提条件，良好的体外溶出使得药品在体内具有更高的药时曲线下面积(AUC)，即药物吸收程度较高，在体内暴露特性良好，从而提高生物利用度，使得药物的疗效更好。较快的体外溶出速率使得药物在体内具有更短的达峰时间(Tmax)和更高的峰浓度(Cmax)，即给药后药物在血浆中能够很快达到最高浓度值，且最高浓度值较高，进而确保药物快速起效并提高药效。
表15
Figure PCTCN2018078766-appb-000012
Figure PCTCN2018078766-appb-000013
3.晶型CS1和CS9在制剂中的稳定性：
取上述制备的片剂在40℃/75％相对湿度条件下放置1个月，经检测，含晶型CS1和晶型CS9在片剂中，晶型未发生变化，结果如下表16所示，说明晶型CS1和晶型CS9在制剂中具有很好的稳定性。
表16 晶型CS1和CS9在制剂中的稳定性
样品 放置条件 放置时间 放置后API晶型
含晶型CS1的片剂 40℃/75％相对湿度 1个月 晶型CS1
含晶型CS9的片剂 40℃/75％相对湿度 1个月 晶型CS9
本发明的晶型CS1和晶型CS9在制剂中稳定性良好，确保其在制剂工艺及制剂储存过程中，不容易转变成其它晶型，从而能够保证药品的质量一致可控。
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 (13)

  1. 一种GSK1278863的晶型CS1，其特征在于，其X射线粉末衍射在衍射角2θ值为6.4°±0.2°、7.5°±0.2°、7.9°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射在衍射角2θ值为17.2°±0.2°、21.0°±0.2°、24.0°±0.2°、19.3°±0.2°中的一处或多处有特征峰。
  3. 一种GSK1278863晶型CS1的制备方法，其特征在于，所述方法为：
    (1)将GSK1278863溶解在环醚类溶剂或酮类溶剂中，在10～50℃下挥发析晶获得；或
    (2)将GSK1278863溶解在环醚类溶剂中，添加反溶剂析晶，后分离、干燥而获得。
  4. 根据权利要求3所述的制备方法，方法(1)中所述环醚类溶剂为四氢呋喃；所述酮类溶剂为丙酮、甲基异丁基酮中的一种或它们的任意混合；所述挥发温度为室温或50℃；方法(2)中所述环醚类溶剂为1,4-二氧六环；所述反溶剂为水；所述析晶时间为0.5～24小时。
  5. 根据权利要求4所述的制备方法，方法(1)中所述酮类溶剂为丙酮或甲基异丁基酮；方法(2)中所述析晶时间为2小时。
  6. 一种GSK1278863的晶型CS9，其特征在于，其X射线粉末衍射在衍射角2θ值为4.6°±0.2°、6.6°±0.2°、21.1°±0.2°处有特征峰。
  7. 根据权利要求6所述的晶型CS9，其特征还在于，其X射线粉末衍射在衍射角2θ值为9.4°±0.2°、20.2°±0.2°、24.2°±0.2°中的一处或多处有特征峰。
  8. 一种GSK1278863晶型CS9的制备方法，其特征在于，所述方法为：
    (1)将GSK1278863溶解在醚类溶剂中，并加入高聚物，在10～70℃下挥发析晶而获得；或
    (2)将GSK1278863溶解在酯类和醇类溶剂的混合体系中，在10～70℃下挥发析晶而获得。
  9. 根据权利要求8所述的制备方法，方法(1)中所述醚类溶剂为甲基叔丁基醚；所述高聚物为由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成的高聚物；所述挥发温度为50℃；方法(2)中所述酯类溶剂为乙酸乙酯；所述醇类溶剂为乙醇；所述酯类溶剂和醇类溶剂的体积比为1:10～10:1；所述挥发温度为50℃。
  10. 根据权利要求9所述的制备方法，方法(2)中所述酯类溶剂和醇类溶剂的体积比为1:1。
  11. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型CS1或权利要求6所述的晶型CS9或它们的任意混合及药学上可接受的载体、稀释剂或赋形剂。
  12. 权利要求1所述的晶型CS1或权利要求6所述的晶型CS9或它们的任意混合在生产制备含缺氧诱导因子脯氨酰羟化酶抑制剂的药物制剂中的用途。
  13. 权利要求1所述的晶型CS1或权利要求6所述的晶型CS9或它们的任意混合在制备用于治疗和/或预防贫血的药物制剂中的用途。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020102302A1 (en) * 2018-11-15 2020-05-22 Teva Pharmaceuticals International Gmbh Solid state forms of daprodustat and process for preparation thereof
WO2021031102A1 (zh) * 2019-08-20 2021-02-25 深圳仁泰医药科技有限公司 Daprodustat的晶型及其制备方法和用途
WO2021255159A1 (en) 2020-06-19 2021-12-23 Glaxosmithkline Intellectual Property (No.2) Limited Formulation comprising daprodustat
WO2022179967A1 (en) 2021-02-23 2022-09-01 Glaxosmithkline Intellectual Property (No.2) Limited Vadadustat for treating covid-19 in a hospitalized subject
WO2022263899A1 (en) 2021-06-18 2022-12-22 Glaxosmithkline Intellectual Property (No.2) Limited Novel manufacturing method of daprodustat and precursors thereof
WO2022269323A1 (en) 2021-06-25 2022-12-29 Glaxosmithkline Intellectual Property (No.2) Limited Daprodustat for reducing fatigue in a subject with anemia associated with chronic kidney disease
US11643397B2 (en) 2006-06-23 2023-05-09 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
WO2024022998A1 (en) 2022-07-26 2024-02-01 Inke, S.A. Process for preparing daprodustat and cocrystals thereof
WO2024028262A1 (en) 2022-08-02 2024-02-08 Glaxosmithkline Intellectual Property (No.2) Limited Novel formulation
WO2024126330A1 (en) 2022-12-13 2024-06-20 Glaxosmithkline Intellectual Property (No.2) Limited Daprodustat for reducing fatigue

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020533396A (ja) * 2017-09-15 2020-11-19 クリスタル ファーマシューティカル（スーチョウ）カンパニー，リミテッド Ｇｓｋ１２７８８６３の結晶形及びその製造方法並びに医薬用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101505752A (zh) 2006-06-23 2009-08-12 史密丝克莱恩比彻姆公司 脯氨酸羟化酶抑制剂

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020071931A (ko) 2000-01-07 2002-09-13 트렌스폼 파마수티컬스 인코퍼레이티드 다양한 고체-형태들의 고도의 자료 처리 편성, 확인 및분석
FR2889383A1 (fr) 2005-08-01 2007-02-02 France Telecom Procede et dispositif de detection pour systeme mimo, systeme mimo, programme et support d'information
US9126724B2 (en) 2013-03-15 2015-09-08 Exopack Llc Child-resistant zipper assemblies and packages utilizing the same
JP2020533396A (ja) * 2017-09-15 2020-11-19 クリスタル ファーマシューティカル（スーチョウ）カンパニー，リミテッド Ｇｓｋ１２７８８６３の結晶形及びその製造方法並びに医薬用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101505752A (zh) 2006-06-23 2009-08-12 史密丝克莱恩比彻姆公司 脯氨酸羟化酶抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG, MINGXIAO ET AL.: "Recent progress of Hypoxia Inducible factor-prolyl Hydroxylase domain containing enzymes inhibitors", JOURNAL OF INTERNATIONAL PHARMACEUTICAL RESEARCH, vol. 43, no. 02, 30 April 2016 (2016-04-30), XP009519874, ISSN: 1674-0440 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11643397B2 (en) 2006-06-23 2023-05-09 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
WO2020102302A1 (en) * 2018-11-15 2020-05-22 Teva Pharmaceuticals International Gmbh Solid state forms of daprodustat and process for preparation thereof
WO2021031102A1 (zh) * 2019-08-20 2021-02-25 深圳仁泰医药科技有限公司 Daprodustat的晶型及其制备方法和用途
CN112752577A (zh) * 2019-08-20 2021-05-04 深圳仁泰医药科技有限公司 Daprodustat的晶型及其制备方法和用途
CN112752577B (zh) * 2019-08-20 2023-07-07 深圳仁泰医药科技有限公司 Daprodustat的晶型及其制备方法和用途
WO2021255159A1 (en) 2020-06-19 2021-12-23 Glaxosmithkline Intellectual Property (No.2) Limited Formulation comprising daprodustat
CN115697307A (zh) * 2020-06-19 2023-02-03 葛兰素史密斯克莱知识产权（第2 号）有限公司 包含达普司他的制剂
WO2022179967A1 (en) 2021-02-23 2022-09-01 Glaxosmithkline Intellectual Property (No.2) Limited Vadadustat for treating covid-19 in a hospitalized subject
WO2022263899A1 (en) 2021-06-18 2022-12-22 Glaxosmithkline Intellectual Property (No.2) Limited Novel manufacturing method of daprodustat and precursors thereof
WO2022269323A1 (en) 2021-06-25 2022-12-29 Glaxosmithkline Intellectual Property (No.2) Limited Daprodustat for reducing fatigue in a subject with anemia associated with chronic kidney disease
WO2024022998A1 (en) 2022-07-26 2024-02-01 Inke, S.A. Process for preparing daprodustat and cocrystals thereof
WO2024028262A1 (en) 2022-08-02 2024-02-08 Glaxosmithkline Intellectual Property (No.2) Limited Novel formulation
WO2024126330A1 (en) 2022-12-13 2024-06-20 Glaxosmithkline Intellectual Property (No.2) Limited Daprodustat for reducing fatigue

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