WO2021203409A1 - 一种用于治疗丙肝的无引湿性低变异性新晶型 - Google Patents

一种用于治疗丙肝的无引湿性低变异性新晶型 Download PDF

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WO2021203409A1
WO2021203409A1 PCT/CN2020/084178 CN2020084178W WO2021203409A1 WO 2021203409 A1 WO2021203409 A1 WO 2021203409A1 CN 2020084178 W CN2020084178 W CN 2020084178W WO 2021203409 A1 WO2021203409 A1 WO 2021203409A1
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compound
crystal form
solvent
preparation
temperature
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French (fr)
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徐丹
东鸿鑫
郑礼康
柴雨柱
赵明礼
朱春霞
王华萍
周莉
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南京正大天晴制药有限公司
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention relates to the field of biomedicine, in particular to a new crystal form of a drug for treating HCV.
  • Hepatitis C virus (HCV) infection is a worldwide epidemic. There are more than 200 million chronically infected people worldwide. The chronic infection rate in Egypt is 15%, Pakistan is 4.8%, and China is 3.2%, ranking among the top three in the world.
  • the clinical manifestations of hepatitis C virus infection are diverse, ranging from inflammation to severe cirrhosis and liver cancer.
  • Chronic hepatitis C can also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, conjunctival keratitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and late onset Skin porphyria, etc., may be caused by the body's abnormal immune response.
  • hepatitis C cirrhosis In the decompensated stage of hepatitis C cirrhosis, various complications can occur, such as ascites and abdominal cavity infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, liver failure and other manifestations.
  • Sofosbuvir English name Sofosbuvir, is a breakthrough drug developed by Gilead Sciences for the treatment of chronic hepatitis C. It was approved by the U.S. Food and Drug Administration in December 2013 and listed in the United States. It was approved by European Drug Administration in January 2014. The Bureau approved the listing in the European Union. Sofosbuvir alone or in combination (in combination with Ledipasvir or Velpatasvir) can treat all-genotype hepatitis C, with a cure rate of more than 95%.
  • Highly variable drugs means that when the intra-individual coefficient of variation CV (intra-individual coefficient of variation calculated by AUC and C max ) of a drug is ⁇ 30%, the drug is defined as highly variable drugs (HVD) . If the test preparation and the reference preparation are bioequivalent, then the geometric mean ratio (GMR) of the bioequivalence indicators (ie AUC and C max) of the two preparations is 90% confident The interval (CI) must fall within the 80%-125% bioequivalence range. According to incomplete statistics, approximately 15% to 20% of the generic drugs declared by the FDA are highly variable drugs. Even if high-variability drugs are compared with reference preparations, there is a risk of bioequivalence. Therefore, the bioequivalence study of highly-variable drugs is a problem that pharmaceutical researchers have been plagued by.
  • the bioequivalence study guideline recommends the bioequivalence test of sofosbuvir tablets in the postprandial state, the dosage is 400mg, the test population is healthy subjects, and the tested ingredients are the original drug.
  • the results show that, The C max of sofosbuvir in the postprandial state showed high variation, with a coefficient of variation as high as 54%.
  • the present invention provides a crystalline form T of compound I.
  • the 2 ⁇ angle of the powder X-ray diffraction pattern of the crystalline form T obtained by using CuKa rays includes characteristic peaks: 5.0° ⁇ 0.2°, 7.2° ⁇ 0.2 °, 9.7° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.3° ⁇ 0.2° and 19.1° ⁇ 0.2°, wherein the structure of the compound I is:
  • the 2 ⁇ angles of the crystalline form T in the powder X-ray diffraction pattern obtained by using CuKa rays include characteristic peaks: 5.0° ⁇ 0.2°, 7.2° ⁇ 0.2°, 9.7° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.3° ⁇ 0.2°, 19.1° ⁇ 0.2°, 21.0° ⁇ 0.2° and 25.2° ⁇ 0.2°.
  • the 2 ⁇ angles of the crystalline form T in the powder X-ray diffraction pattern obtained by using CuKa rays include characteristic peaks: 5.0° ⁇ 0.2°, 7.2° ⁇ 0.2°, 9.7° ⁇ 0.2°, 10.0° ⁇ 0.2°, 10.3° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.0° ⁇ 0.2 °, 23.2° ⁇ 0.2°, 24.6° ⁇ 0.2° and 25.2° ⁇ 0.2°.
  • the crystal form T has an X-ray diffraction pattern as shown in FIG. 1 obtained by using CuKa rays.
  • the present invention provides a method for preparing crystal form T: adding compound I to a solvent selected from 4-methyl-2-pentanone, cyclohexanone or 2-butanone, and dissolving at elevated temperature , Heat preservation and stirring, slowly add a small amount of anti-solvent, slowly cool down for the first time, stir, and then quickly add a large amount of anti-solvent, further slowly cool down, stir and crystallize, and filter to obtain a white solid, which is compound I crystal form T, in which The anti-solvent is selected from one of ethyl acetate, butyl acetate or isopropyl acetate.
  • the temperature of the temperature-rising dissolution is 45-55°C, preferably 45°C, 50°C, or 55°C.
  • the first slow cooling down is to 20-25°C; preferably 20°C or 25°C.
  • the further slow cooling is reduced to 10-15°C; preferably 10°C or 15°C.
  • the stirring speed is 200-300 revolutions per minute; preferably 200 revolutions per minute, 250 revolutions per minute or 300 revolutions per minute.
  • the volume of the small amount of anti-solvent is 20-40% of the volume of the solvent that dissolves Compound I, preferably 20%, 25%, 30%, 35% or 40%.
  • the volume of the large amount of anti-solvent is 3-5 times the volume of the solvent for dissolving Compound I, preferably 3 times, 3.5 times, 4 times, 4.5 times or 5 times.
  • the present invention provides a pharmaceutical composition, which contains compound I crystal form T and pharmaceutically acceptable excipients.
  • the pharmaceutical composition contains compound I crystalline form T, mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
  • the pharmaceutical composition by weight, contains 20-40% compound I crystal form T, 20-40% mannitol, 20-40% microcrystalline cellulose, 2-8% Of croscarmellose sodium, 0.2-2% colloidal silicon dioxide and 1-3% magnesium stearate.
  • the pharmaceutical composition by weight, contains 33.33% of compound I crystal form T, 30.00% of mannitol, 29.67% of microcrystalline cellulose, and 5.00% of croscarmellose Sodium, 0.50% colloidal silicon dioxide and 1.50% magnesium stearate.
  • the present invention provides a pharmaceutical preparation, the active ingredient of which comprises the above-mentioned compound I crystal form T, and other pharmaceutically acceptable excipients.
  • the types of pharmaceutical preparations described in the present invention include, but are not limited to: tablets, capsules, granules, solution types and the like.
  • the administration route of the pharmaceutical preparations of the present invention is based on typical gastrointestinal administration, but other possible administration routes, such as injection administration, respiratory administration, etc., are not excluded.
  • the new crystal form T recorded in the present invention has simple crystallization process, easy industrial production, and no hygroscopicity. After the crystal form T is further prepared into a suitable preparation, the coefficient of variation of the subject's postprandial C max can be significantly reduced, so that the safety and effectiveness of the drug can be more reliably guaranteed.
  • Figure 1 is an X-ray diffraction pattern of compound I crystal form T using CuKa rays.
  • the crystalline product has an X-ray diffraction pattern as shown in Figure 1 obtained using CuKa rays (the X-ray powder diffraction pattern was collected on the following equipment: D8Advance powder diffractometer, the diffractometer using CuK ⁇ rays ( 40kV, 40mA), theta-theta goniometer, 0.6mm divergence slit, 2.5mm solar slit, 0.02mm nickel sheet, one-dimensional array detector. The device uses the certified corundum standard (SRM1976b) for performance Inspection. The software used for data collection is DIFFRAC.COMMANDER, and the detection data is analyzed and presented using DIFFRAC.EVAV4.3.221CFR Part11).
  • crystal form T The hygroscopicity of crystal form T, crystal form I and crystal form VI was studied according to the following method. Among them, the crystal form I and the crystal form VI are prepared by the method described in the patent with the publication number CN104039319B.
  • Sieving I After mixing, the mixture is sieved with a crushing and sizing machine with a sieve aperture of 2.0mm and a sizing machine speed of 500r/min.
  • Sieving II Add 0.06kg of colloidal silicon dioxide and 6kg of microcrystalline cellulose into the hopper of the crushing and sizing machine in order for sieving.
  • the sieve aperture is 2.0mm and the speed of the sizing machine is 500r/min.
  • Pre-mixing Add the pre-treated internal material mixture (the product obtained by sieving II) and 0.9 kg of magnesium stearate into the mixing hopper, set the mixing speed to 10r/min, and the mixing time for 10 minutes.
  • Dry granulation the premixed mixture is added to the dry granulator for granulation.
  • the granulating parameters feeding speed (8-12) r/min, extrusion speed (8-12) r/min, granulating speed (95 ⁇ 125)r/min, extrusion pressure (8 ⁇ 12)kN, side seal pressure (10 ⁇ 20)kN, sieve mesh number is 24 mesh.
  • Total mixing In the mixing hopper, add dry granulation materials, pretreatment external auxiliary materials, croscarmellose 3kg, magnesium stearate 0.9kg, set mixing speed 10r/min, mixing time 15min.
  • the content is 31.7%-34.9%, and the moisture content is less than or equal to 4.0%.
  • Tableting Calculate the standard tablet weight based on the determination of the intermediate content.
  • the tableting die is a special shaped punch. Adjust the filling depth, pre-pressing thickness and main pressing thickness so that the pre-pressing pressure is ⁇ 7.0KN, the host pressure is (13.0 ⁇ 24.0)kN, and the production speed is (45 ⁇ 5)kT/ h. In the process, control the appearance, average tablet weight, tablet weight difference, hardness and disintegration time limit to meet the requirements.
  • the appearance of the plain tablets should be consistent, the surface should be complete and smooth, the edges should be neat, and the color should be uniform. There should be no discoloration, stains or pitting; the difference of the tablet weight should be controlled by ⁇ 3.5%, and the weight of each tablet should be within the control range of the tablet weight; The control range is 200N ⁇ 300N; the disintegration time limit is to control all 6 tablets in water to disintegrate within 15min.
  • Coating Prepare a film coating solution (gastric-soluble Opadry) with a concentration of 15% (w/w) and use it after swelling and dispersing for 1 hour.
  • the host speed is controlled at 1.6r/min ⁇ 5.0r/min, and the hot air will be stopped after drying for 10 minutes. When the temperature drops to room temperature, the film will be stopped.
  • the appearance of the coating intermediate product should be uniform in color, smooth in surface, no adhesion, no coating liquid falling off, etc., and the weight gain of the coating should be controlled at 2.0% to 4.0%.
  • the final product contains 400mg of Compound I per tablet.
  • the subjects’ blood collection time points are: 0h before taking the medicine (within 1h before taking the medicine, before eating) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, after taking the medicine in each cycle. 3 mL of venous blood was collected at 20 blood collection points at 5, 6, 8, 12, 24, 48, and 72 hours.
  • the experimental results show that the subject takes the tablet prepared in Preparation Preparation Example 1 (that is, the compound I crystal form T is used as the raw material) , and the coefficient of variation CV of C max after a meal is only 24.6%, which is less than 30%. However, for the tablets prepared with compound crystal form I or crystal form VI, the coefficient of variation CV of C max after the meal of the subjects were all higher than 50%. The results of this experiment are consistent with the subjects taking the FDA listed drugs The results obtained are consistent.
  • the crystal form of compound I obtained in the present invention has the following advantages: no hygroscopicity, low variability, and it has significant advantages for treating chronic hepatitis C.

Abstract

一种用于治疗丙肝的无引湿性低变异性新晶型，新晶型T结晶工艺简便，易于工业化生产，无引湿性。使用该晶型T进一步制备成合适的制剂后，能够显著降低受试者餐后Cmax的变异系数，使药品的安全性有效性得到更可靠的保障。

Description

一种用于治疗丙肝的无引湿性低变异性新晶型 技术领域
本发明涉及生物医药领域，具体为一种治疗HCV的药物的新晶型。
背景技术
丙型肝炎病毒(HCV)感染是世界范围内流行的疾病，全球慢性感染者已超过2亿，埃及的慢性感染率为15％，巴基斯坦为4.8％，中国为3.2％，位列世界前三。丙型肝炎病毒感染的临床表现多样，轻至炎症，重至肝硬化、肝癌。慢性丙型肝炎还可以并发某些肝外表现，包括类风湿性关节炎、干燥性结膜角膜炎、扁平苔藓、肾小球肾炎、混合型冷球蛋白血症、B细胞淋巴瘤和迟发性皮肤卟啉症等，可能是机体异常免疫反应所致。且丙肝肝硬化失代偿期时，可以出现各种并发症，如腹水腹腔感染，上消化道出血，肝性脑病，肝肾综合征，肝衰竭等表现。
索磷布韦，英文名为Sofosbuvir，是吉利德科学公司开发用于治疗慢性丙型肝炎的突破性药物，2013年12月经美国食品药品监督管理局批准在美国上市，2014年1月经欧洲药品管理局批准在欧盟上市。索非布韦单独使用或复方(联合Ledipasvir或Velpatasvir)能治疗全基因型丙肝，治愈率在95％以上。
高变异药物是指当某一药物的个体内变异系数CV(以AUC和C max计算的个体内变异系数)≥30％时，该药物被定义为高变异性的药物(highly variable drugs，HVD)。如果受试制剂和参比制剂之间是生物等效的，那么两种制剂的生物等效性指标(即AUC和C max)的几何均数比例(the geometric mean ratio，GMR)的90％置信区间(CI)必须落入80％～125％的生物等效性范围内。据不完全统计，FDA申报的仿制药中大约有15％～20％的药物属于高变异性药物。高变异性药物即使采用参比制剂自身比较，也会存在生物不等效的风险，因此，高变异药物的生物等效性研究，是药学研究者们一直困扰的难题。
世界卫生组织(WHO)对索氟布韦片
Figure PCTCN2020084178-appb-000001
的生物等效性研究指南推荐进行索氟布韦片餐后状态下的生物等效性试验，给药剂量为400mg，受试人群为健康受试者，检测的成分为原形药物，结果显示，餐后状态下索氟布韦的C max显示出高变异，变异系数高达54％。
发明内容
一方面，本发明提供了一种化合物I的晶型T，所述晶型T在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°和19.1°±0.2°，其中所述化合物I结构为：
Figure PCTCN2020084178-appb-000002
在一些实施方案中，所述晶型T在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°、19.1°±0.2°、21.0°±0.2°和25.2°±0.2°。
在一些实施方案中，所述晶型T在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°、16.1°±0.2°、16.9°±0.2°、18.3°±0.2°、19.1°±0.2°、20.1°±0.2°、20.6°±0.2°、21.0°±0.2°、23.2°±0.2°、24.6°±0.2°和25.2°±0.2°。
在一些实施方案中，所述晶型T具有使用CuKa射线得到的如图1所示的X射线衍射图谱。
另一方面，本发明提供了一种晶型T的制备方法：将化合物I加入至选自4-甲基-2-戊酮、环己酮或2-丁酮的一种溶剂中，升温溶解，保温搅拌，缓慢滴加少量反溶剂，第一次缓慢降温，搅拌，再快速滴加大量反溶剂，进一步缓慢降温，搅拌析晶，过滤，得白色固体，即为化合物I晶型T，其中所述反溶剂选自乙酸乙酯、乙酸丁酯或乙酸异丙酯中的一种。
在一些实施方案中，所述升温溶解的温度为45-55℃，优选为45℃、50℃或55℃。
在一些实施方案中，所述第一次缓慢降温为降至20-25℃；优选为20℃或25℃。
在一些实施方案中，所述进一步缓慢降温为降至10-15℃；优选为10℃或 15℃。
在一些实施方案中，所述搅拌的速度均为200-300转/分钟；优选为200转/分钟、250转/分钟或300转/分钟。
在一些实施方案中，所述少量反溶剂的体积为溶解化合物I溶剂体积的20～40％，优选为20％、25％、30％、35％或40％。
在一些实施方案中，所述大量反溶剂的体积为溶解化合物I溶剂体积的3-5倍，优选为3倍、3.5倍、4倍、4.5倍或5倍。
另一方面，本发明提供了一种药物组合物，所述药物组合物含有化合物I晶型T和药学上可接受的辅料。
在一些实施方案中，所述药物组合物含有化合物I晶型T、甘露醇、微晶纤维素、交联羧甲基纤维素钠、胶态二氧化硅和硬脂酸镁。
在一些实施方案中，所述药物组合物，按重量计，含有20-40％的化合物I晶型T、20-40％的甘露醇、20-40％的微晶纤维素、2-8％的交联羧甲基纤维素钠、0.2-2％的胶态二氧化硅和1-3％的硬脂酸镁。
在一些实施方案中，所述药物组合物，按重量计，含有33.33％的化合物I晶型T、30.00％的甘露醇、29.67％的微晶纤维素、5.00％的交联羧甲基纤维素钠、0.50％的胶态二氧化硅和1.50％的硬脂酸镁。
另一方面，本发明提供了一种药物制剂，该制剂的有效成分包含上述的化合物I晶型T，以及其他药学上可接受的辅料。
本发明所述的药物制剂类型包括但不限于：片剂、胶囊、颗粒剂、溶液型等。
本发明所述的药物制剂的给药途径以典型的胃肠道给药为主，但并不排除其他可能的给药途径，例如注射给药、呼吸道给药等。
本发明记载的新晶型T，结晶工艺简便，易于工业化生产，无引湿性。使用该晶型T进一步制备成合适的制剂后，能够显著降低受试者餐后C max的变异系数，使药品的安全性有效性得到更可靠的保障。
附图说明
通过阅读下文优选实施方式的详细描述，各种其他的优点和益处对于本领 域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本发明的限制。而且在整个附图中，用相同的参考符号表示相同的部件。
图1为化合物I晶型T使用CuKa射线得到的X射线衍射图谱。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
晶型制备例1
将化合物I 4.0g加入至10ml环己酮溶液中，升温至55℃溶解，保温搅拌，搅拌速度为200r/min，缓慢滴加乙酸乙酯2ml，再缓慢降温至20℃，保温搅拌2h后，再快速加入乙酸乙酯35ml，缓慢降温至10℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，即化合物I晶型T，共计3.69g，纯度大于为99.5％。经过检测，该晶型产物具有使用CuKa射线得到的如图1所示的X射线衍射图谱(X-射线粉末衍射图谱在下列设备上进行收集：D8Advance粉末衍射仪，所述衍射仪使用CuKα射线(40kV，40mA)，theta-theta测角仪，0.6mm发散狭缝，2.5mm索拉狭缝，0.02mm镍片，一维阵列探测器。所述装置使用认证的刚玉标准(SRM1976b)来进行性能检查。用于数据收集的软件是DIFFRAC.COMMANDER，检测数据使用DIFFRAC.EVAV4.3.221CFR Part11进行分析和呈现)。
晶型制备例2
将化合物I 4.0g加入至10ml 2-丁酮溶液中，升温至45℃溶解，保温搅拌，搅拌速度为300r/min，缓慢滴加乙酸丁酯3ml，再缓慢降温至25℃，保温搅拌2h后，再快速加入乙酸丁酯30ml，缓慢降温至15℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，即化合物I晶型T，共计3.62g，纯度大于为99.5％。经X射线粉末衍射分析，其图谱与制备例1所得样品的图谱一致。
晶型制备例3
将化合物I 4.0g加入至10ml 4-甲基-2-戊酮溶液中，升温至50℃溶解，保温搅拌，搅拌速度为250r/min，缓慢滴加乙酸异丙酯4ml，再缓慢降温至20℃，保温搅拌2h后，再快速加入乙酸异丙酯40ml，缓慢降温至10℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，即化合物I晶型T，共计3.74g，纯度大于为99.5％。经X射线粉末衍射分析，其图谱与制备例1所得样品的图谱一致。
晶型制备例4
将化合物I 4.0g加入至10ml环己酮溶液中，升温至50℃溶解，保温搅拌，搅拌速度为250r/min，缓慢滴加乙酸异丙酯3ml，再缓慢降温至20℃，保温搅拌2h后，再快速加入乙酸异丙酯50ml，缓慢降温至10℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，即化合物I晶型T，共计3.66g，纯度大于为99.5％。经X射线粉末衍射分析，其图谱与制备例1所得样品的图谱一致。
晶型制备例5
将化合物I 4.0g加入至10ml环己酮溶液中，升温至50℃溶解，保温搅拌，搅拌速度为250r/min，缓慢滴加乙酸异丙酯4ml，再缓慢降温至20℃，保温搅拌2h后，再快速加入乙酸乙酯45ml，缓慢降温至10℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，即化合物I晶型T，共计3.79g，纯度大于为99.5％。经X射线粉末衍射分析，其图谱与制备例1所得样品的图谱一致。
晶型制备例6
将化合物I 4.0g加入至10ml环己酮溶液中，升温至55℃溶解，保温搅拌，搅拌速度为200r/min，缓慢滴加乙酸乙酯40ml，缓慢降温至25℃，保温搅拌析晶析晶，过滤，所得滤饼50℃下真空干燥，得白色固体，经检测，该产物XRPD图谱与晶型T的XRPD谱图差异较大。
晶型制备例7
将化合物I 4.0g加入至10ml 4-甲基-2-戊酮溶液中，升温至55℃溶解，保温搅拌，搅拌速度为250r/min，缓慢滴加乙酸异丙酯35ml，缓慢降温至10℃， 保温搅拌析晶析晶，过滤，所得滤饼50℃下真空干燥，得白色固体，经检测，该产物XRPD图谱与晶型T的XRPD谱图差异较大。
晶型制备例8
将化合物I 4.0g加入至10ml丙酮溶液中，升温至50℃溶解，保温搅拌，搅拌速度为250r/min，缓慢滴加乙酸乙酯4ml，再缓慢降温至20℃，保温搅拌2h后，再快速加入乙酸乙酯40ml，缓慢降温至10℃，保温搅拌析晶2h后，过滤，所得滤饼50℃下真空干燥，得白色固体，经检测，该产物XRPD图谱与晶型T的XRPD谱图差异较大。
引湿性研究
按照如下方法研究晶型T、晶型I和晶型VI的引湿性。其中晶型I和晶型VI经由公开号为CN104039319B的专利记载的方法制备而来。
取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于人工气候箱(设定温度为25℃±1℃，相对湿度为80％±2％)内，精密称定，重量记为m 1。取供试品适量，平铺于上述称量瓶中，供试品厚度约为1mm，精密称定，重量记为m 2。将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24小时。盖好称量瓶盖子，精密称定，重量记为m 3。增重百分率(M)＝(m 3-m 2)/(m 2-m 1)×100％。
Figure PCTCN2020084178-appb-000003
制剂制备例1
混合：化合物I晶型T 40kg、甘露醇36kg、微晶纤维素29.6kg、交联羧甲基纤维素钠3kg、胶态二氧化硅0.54kg加入混合料斗内，设置混合转速10r/min，混合时间30min。
过筛I：混合结束后将混合物采用粉碎整粒机过筛，筛网孔径2.0mm，整粒机转速500r/min。
过筛II：将胶态二氧化硅0.06kg、微晶纤维素6kg按顺序加入到粉碎整粒机料斗中过筛，筛网孔径2.0mm，整粒机转速500r/min。
预混：在混合料斗中加入预处理后的内加物料混合物(即过筛II得到的产 物)和硬脂酸镁0.9kg，设置混合转速10r/min，混合时间10min。
干法制粒：将预混后的混合物加入干法制粒机进行制粒，制粒参数送料转速(8～12)r/min，挤压转速(8～12)r/min，制粒转速(95～125)r/min，挤压压力(8～12)kN，侧封压力(10～20)kN，筛网目数为24目。
总混：在混合料斗内加入干法制粒后物料、预处理后的外加辅料、交联羧甲基纤维素3kg、硬脂酸镁0.9kg，设置混合转速10r/min，混合时间15min。
总混结束后取样检测中间产品含量和水分，合格标准：含量31.7％～34.9％，水分≤4.0％。
压片：根据中间体含量测定计算标准片重。压片模具为专用异形冲，调整充填深度、预压片厚和主压片厚，使预压压力≤7.0KN，主机压力为(13.0～24.0)kN，生产速度为(45±5)kT/h，过程中控制外观、平均片重、片重差异、硬度与崩解时限符合要求。
素片外观应片形一致，表面完整光洁，边缘整齐，色泽均匀，不得有变色、色斑或麻点等现象；片重差异控制±3.5％，每片重量均在片重控制范围内；硬度控制范围为200N～300N；崩解时限控制水中6片15min内全部崩解。
包衣：配制浓度为15％(w/w)的薄膜包衣液(胃溶型欧巴代)，溶胀分散1h后使用。
开机预热，控制主机转速在1.6r/min～5.0r/min范围，负压在40Pa～100Pa范围，调整热风柜温度使入口温度达到55℃～80℃，将压片中间产品加入包衣锅内，片芯预热并自动除粉，至片床温度合格后开始包衣操作。
开启包衣操作，控制主机转速1.6r/min～11.0r/min，蠕动泵流量300ml/min～800ml/min，雾化压力0.45MPa～0.50MPa，片床温度37℃～43℃，负压40Pa～100Pa。包衣过程中随时检查外观。
喷液结束时，主机转速控制在1.6r/min～5.0r/min，干燥10min后停止吹热风，待温度降至室温时，停机出片。
包衣中间产品外观应色泽均匀，表面光滑，无粘连、无包衣液脱落等现象，包衣增重控制在2.0％～4.0％。终产品每片含化合物I 400mg。
制剂制备例2
采用与制剂制备例1相同制备方法，分别制备主药为化合物I晶型I的制 剂，各辅料用量与制剂制备例1相同。其中晶型I经由公开号为CN104039319B的专利记载的方法制备而来。
制剂制备例3
采用与制剂制备例1相同制备方法，分别制备主药为化合物I晶型VI的制剂，各辅料用量与制剂制备例1相同。其中晶型VI经由公开号为CN104039319B的专利记载的方法制备而来。
不同化合物I晶型变异系数的测定
将45名健康受试者随机分为3组(n＝15)，每组受试者在餐后状态下分别服用制剂制备例1-3制备得到的片剂1片(每片含化合物I 400mg)。在给药前于受试者前臂放置静脉留置针，每次采集血样前，需要弃去约0.5mL血液后再采集血样，并用适量肝素钠溶液封管。
受试者的采血时间点为：每周期服药前0h(服药前1h内，进食前)和服药后0.25、0.5、0.75、1、1.25、1.5、1.75、2、2.5、3、3.5、4、5、6、8、12、24、48h和72h共20个采血点采集静脉血3mL。
取静脉血并测定血浆中化合物I的含量，得到C max值并计算每组个体内变异系数CV，结果如下表。
组别 C max变异系数CV
制剂制备例1 24.6％
制剂制备例2 56.4％
制剂制备例3 55.9％
实验结果显示，受试者服用制剂制备例1制得的片剂(即采用化合物I晶型T作为原料药)餐后C max的变异系数CV仅为24.6％，低于30％。而采用化合物晶型I或晶型VI制备得到的片剂，受试者餐后C max的变异系数CV均高于50％，该实验结果与受试者服用FDA上市药物
Figure PCTCN2020084178-appb-000004
得到的结果一致。
综上，经检测，本发明获得的化合物I的晶型具有以下优点：无引湿性、低变异性，其用于治疗慢性丙型肝炎具有显著优势。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局 限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (11)

  1. 一种化合物I的晶型T，所述晶型T在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°和19.1°±0.2°，其中所述化合物I结构为：
    Figure PCTCN2020084178-appb-100001
  2. 如权利要求1所述的晶型T，在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°、19.1°±0.2°、21.0°±0.2°和25.2°±0.2°。
  3. 如权利要求1所述的晶型T，在使用CuKa射线得到的粉末X射线衍射图谱中的2θ角包含特征峰：5.0°±0.2°、7.2°±0.2°、9.7°±0.2°、10.0°±0.2°、10.3°±0.2°、16.1°±0.2°、16.9°±0.2°、18.3°±0.2°、19.1°±0.2°、20.1°±0.2°、20.6°±0.2°、21.0°±0.2°、23.2°±0.2°、24.6°±0.2°和25.2°±0.2°。
  4. 如权利要求1所述的晶型T，具有使用CuKa射线得到的如图1所示的X射线衍射图谱。
  5. 一种如权利要求1-4任意一项所述的晶型T的制备方法，其特征在于，将化合物I加入至选自4-甲基-2-戊酮、环己酮或2-丁酮的至少一种溶剂中，升温溶解，保温搅拌，缓慢滴加少量反溶剂，第一次缓慢降温，搅拌，再快速滴加大量反溶剂，进一步缓慢降温，搅拌析晶，过滤，得白色固体，即为化合物I晶型T，其中所述反溶剂选自乙酸乙酯、乙酸丁酯或乙酸异丙酯中的一种。
  6. 如权利要求5所述的制备方法，其特征在于，所述升温溶解的温度为45-55℃，优选为45℃、50℃或55℃；所述第一次缓慢降温为降至20-25℃，优选为20℃或25℃；所述进一步缓慢降温为降至10-15℃，优选为10℃或15℃。
  7. 如权利要求5所述的制备方法，其特征在于，所述搅拌的速度均为200-300转/分钟，优选为200转/分钟、250转/分钟或300转/分钟。
  8. 如权利要求5所述的制备方法，其特征在于，所述少量反溶剂的体积为溶解化合物I溶剂体积的20～40％，优选为20％、25％、30％、35％或40％。
  9. 如权利要求5所述的制备方法，其特征在于，所述大量反溶剂的体积为溶解化合物I溶剂体积的3-5倍，优选为3倍、3.5倍、4倍、4.5倍或5倍。
  10. 一种如权利要求1-4任意一项所述的晶型T在制备用于治疗丙肝的药物组合物或药物制剂中的应用。
  11. 权利要求1-4任意一项所述的晶型T治疗丙肝的用途。
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CN104447924A (zh) * 2014-11-07 2015-03-25 南京旗昌医药科技有限公司 索氟布韦的晶型及其制备方法
WO2017158624A1 (en) * 2016-03-17 2017-09-21 Mylan Laboratories Limited Polymorphic forms of sofosbuvir
CN110981910A (zh) * 2019-12-23 2020-04-10 南京正大天晴制药有限公司 一种用于治疗丙肝的无引湿性低变异性新晶型

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