[go: up one dir, main page]

WO2018233678A1 - 右旋雷贝拉唑钠化合物及其药物组合物 - Google Patents

右旋雷贝拉唑钠化合物及其药物组合物 Download PDF

Info

Publication number
WO2018233678A1
WO2018233678A1 PCT/CN2018/092347 CN2018092347W WO2018233678A1 WO 2018233678 A1 WO2018233678 A1 WO 2018233678A1 CN 2018092347 W CN2018092347 W CN 2018092347W WO 2018233678 A1 WO2018233678 A1 WO 2018233678A1
Authority
WO
WIPO (PCT)
Prior art keywords
handed
rabeprazole sodium
crystal form
solvent
rabeprazole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/092347
Other languages
English (en)
French (fr)
Inventor
陈祥峰
陈虹宇
李晓昕
潘讯
孙敏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Hairun Pharmaceutical Co Ltd
Jiangsu Aosaikang Pharmaceutical Co Ltd
Original Assignee
Nanjing Hairun Pharmaceutical Co Ltd
Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201710485939.5A external-priority patent/CN109111428A/zh
Priority claimed from CN201710487802.3A external-priority patent/CN109111429A/zh
Application filed by Nanjing Hairun Pharmaceutical Co Ltd, Jiangsu Aosaikang Pharmaceutical Co Ltd filed Critical Nanjing Hairun Pharmaceutical Co Ltd
Priority to US16/624,740 priority Critical patent/US11078184B2/en
Publication of WO2018233678A1 publication Critical patent/WO2018233678A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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 belongs to the field of medicine, and particularly relates to a novel crystal form of a right-handed rabeprazole sodium compound and a preparation method thereof, and a pharmaceutical composition containing the compound of the right-handed rabeprazole sodium.
  • Dexrabeprazole sodium (Formula I), chemical name R-(+)-2- ⁇ [4-(3-methoxypropoxy)-3-methylpyridin-2-yl] Sodium sulfinyl ⁇ -1H-benzimidazole sodium salt, first developed by EMCURE Pharmaceuticals of India, launched in India in September 2007 for the treatment of gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux Esophagitis, Zollinger-Ellison syndrome, gastrin-dumal duodenal ulcer, benign active gastric ulcer, erosive or ulcerative gastric-esophageal reflux with clinical symptoms Proof that combined with appropriate antibiotics can cure Helicobacter pylori-positive duodenal ulcers.
  • CN104910135A discloses an amorphous form of right-handed rabeprazole sodium, but with poor stability and is not suitable for the preparation of solid preparations.
  • CN102924434A discloses a monohydrate crystal form of dextro-prabeprazole sodium which is a relatively stable crystalline form as disclosed. In addition, no other crystal forms of levofloxacin sodium have been found. In order to improve the quality of the right-handed rabeprazole sodium preparation, it is of great significance to further study the development of the dominant drug crystal form of levofloxacin sodium.
  • the present invention provides a crystalline form B of a right-handed rabeprazole sodium compound, which uses Cu target radiation, and has an X-ray powder diffraction (XRPD) pattern expressed at a 2 ⁇ angle of about 6.50 ⁇ 0.2, 8.64 ⁇ 0.2 Characteristic peaks at 14.46 ⁇ 0.2, 15.92 ⁇ 0.2, 17.74 ⁇ 0.2, 18.40 ⁇ 0.2, 19.58 ⁇ 0.2, and 23.46 ⁇ 0.2 degrees. The peak with the highest relative intensity is a characteristic peak of about 23.46 ⁇ 0.2 degrees.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern is about 6.50 ⁇ 0.2, 8.64 ⁇ 0.2, 10.58 ⁇ 0.2, 13.14 ⁇ 0.2, 14.46 ⁇ 0.2, 14.90 ⁇ 0.2, 15.48 ⁇ 0.2, 15.92 ⁇ 0.2, 16.86 ⁇ 0.2, 17.74.
  • the B crystal form of the right-handed rabeprazole sodium has an XRPD pattern substantially as shown in FIG.
  • the 2 ⁇ angle allows an error of ⁇ 0.2 degrees.
  • the differential scanning calorimetry (DSC) pattern of the B crystal form of the right-handed rabeprazole sodium compound has an endothermic peak at about 138 ° C and an exothermic peak at about 189 ° C and about 226 ° C. Wherein the temperature allows an error of ⁇ 5 °C.
  • the B crystal form of the right-handed rabeprazole sodium compound has a DSC chart substantially as shown in FIG.
  • the B crystal form of the right-handed rabeprazole sodium compound has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG.
  • the B crystal form of the right-handed rabeprazole sodium compound has an infrared (IR) spectrum substantially as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form B of a right-handed rabeprazole sodium compound represented by the formula (I), comprising:
  • the organic solvent of step 1) is selected from the group consisting of dichloromethane, chloroform and ethyl acetate, preferably dichloromethane.
  • the alcohol solvent of step 2) is selected from the group consisting of isopropanol, n-propanol and n-butanol, preferably isopropanol.
  • the antisolvent of step 3) is selected from the group consisting of isopropyl ether, methyl tert-butyl ether, diethyl ether and methyl ethyl ether, preferably isopropyl ether.
  • the ratio of the right-handed rabeprazole to the organic solvent in the step 1) may be 1 g: (1 to 10) ml, such as 1 g: (3 to 5) ml.
  • the ratio of the right-handed rabeprazole to the alcohol solvent in step 2) may be 1 g: (1 to 10) ml, such as 1 g: (3 to 5) ml.
  • the concentration of aqueous sodium hydroxide solution in step 2) is 40% by weight.
  • the amount of the anti-solvent in step 3) is from 1 to 5 times, such as from 2 to 3 times the volume of the reaction solution.
  • the reaction solution may be first concentrated to reduce the volume, and then the anti-solvent may be added dropwise. Concentration is to shrink the solution to any partial volume, such as 1/2 volume, 1/3 volume, 1/4 volume, 1/5 volume, and the like. After the reaction solution is concentrated, the anti-solvent is decanted, and the amount of the anti-solvent can be reduced accordingly, and the crystallization process is accelerated. Concentration can be carried out at 35 to 45 °C.
  • the dropwise addition of the anti-solvent in step 3) can be carried out under low temperature conditions, and the low temperature can be 10 ° C or less.
  • the reaction liquid is cooled to 0 to 10 ° C, preferably 0 to 5 ° C, and an anti-solvent is decanted.
  • the present invention provides a crystalline form C of a right-handed rabeprazole sodium compound using Cu target radiation, an X-ray powder diffraction (XRPD) pattern expressed at a 2 ⁇ angle of about 6.22 ⁇ 0.2, 12.14 ⁇
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern is about 6.22 ⁇ 0.2, 12.14 ⁇ 0.2, 12.46 ⁇ 0.2, 13.10 ⁇ 0.2, 15.82 ⁇ 0.2, 17.34 ⁇ 0.2, 17.70 ⁇ 0.2, 18.90 ⁇ 0.2, 20.18 ⁇ 0.2, 20.74.
  • the C crystal form of the right-handed rabeprazole sodium compound has an XRPD pattern substantially as shown in FIG.
  • the 2 ⁇ angle allows an error of ⁇ 0.2 degrees.
  • the differential scanning calorimetry (DSC) pattern of the C crystal form of the right-handed rabeprazole sodium compound has an exothermic peak at about 234 °C. Wherein the temperature allows an error of ⁇ 5 °C.
  • the C crystal form of the right-handed rabeprazole sodium compound has a DSC pattern substantially as shown in FIG.
  • the C crystal form of the right-handed rabeprazole sodium compound has a TGA pattern substantially as shown in FIG.
  • the C crystal form of the right-handed rabeprazole sodium compound has an IR pattern substantially as shown in FIG.
  • the present invention also provides a method for preparing the C crystal form of the right-handed rabeprazole sodium compound represented by the formula (I), comprising the steps of:
  • step 2) adding acetonitrile to the residue obtained in step 1), stirring, and concentrating to dryness under reduced pressure;
  • the right-handed rabeprazole sodium is dissolved in methanol in the step 1).
  • the number of repetitions of the dissolving and concentrating operations of step 1) is preferably from 1 to 6 times, more preferably from 2 to 5, such as from 3-4 times.
  • the agitation crystallization of step 3) is carried out under the protection of an inert gas, such as nitrogen.
  • the ratio of the right-handed rabeprazole sodium to the organic solvent in step 1) may be 1 g: (1-20) ml, such as 1 g: (3-10) ml.
  • the ratio of the right-handed rabeprazole sodium to the acetonitrile in step 2) may be 1 g: (1-20) ml, such as 1 g: (3-10) ml.
  • the ratio of the right-handed rabeprazole sodium to the solvent in step 3) may be 1 g: (5-30) ml.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described crystalline form of the right-handed rabeprazole sodium compound and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be formulated into any dosage form, preferably an oral preparation such as an enteric tablet, a capsule or the like, or an injection preparation such as a lyophilized powder injection.
  • the present invention also provides the use of the above-described D-Rarebeprazole sodium compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment or prevention of gastrointestinal diseases.
  • gastrointestinal diseases for example, gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, Zollinger-Ellison syndrome (gastrin), active duodenal ulcer, benign active stomach Ulcers, erosive or ulcerative gastric-esophageal reflux syndrome with clinical symptoms, combined with appropriate antibiotics can cure Helicobacter pylori-positive duodenal ulcers.
  • the B crystal form of the right-handed rabeprazole sodium of the present invention exhibits good stability and good fluidity, and is particularly suitable for the preparation of an oral preparation, which can improve the uniformity and quality stability of the preparation.
  • the crystal form of the right-handed rabeprazole sodium C of the invention is an anhydrous crystal type, has low moisture content and is not easy to absorb moisture, has excellent stability, and is suitable for preparing a pharmaceutical preparation.
  • Figure 1 is an XRPD pattern of the B crystal form of the right-handed rabeprazole sodium compound.
  • Figure 2 is a DSC chart of the B crystal form of the right-handed rabeprazole sodium compound.
  • Figure 3 is a TGA diagram of Form B of the right-handed rabeprazole sodium compound.
  • Figure 4 is an IR chart of the B crystal form of the right-handed rabeprazole sodium compound.
  • Figure 5 is an electron micrograph of the B crystal form of the right-handed rabeprazole sodium compound.
  • Figure 6 is an XRPD pattern of Form C of the right-handed rabeprazole sodium compound.
  • Figure 7 is a DSC chart of the C crystal form of the right-handed rabeprazole sodium compound.
  • Figure 8 is a TGA diagram of Form C of the right-handed rabeprazole sodium compound.
  • Figure 9 is an IR chart of the C crystal form of the right-handed rabeprazole sodium compound.
  • Figure 10 is an XRPD pattern of Form A of the D-Rabeprazole sodium compound.
  • Figure 11 is an electron micrograph of the crystal form A of the right-handed rabeprazole sodium compound.
  • Figure 12 is an XRPD pattern of the amorphous state of the right-handed rabeprazole sodium compound.
  • Figure 13 is an XRPD pattern of different crystal forms of the right-handed rabeprazole sodium compound under grinding/high temperature conditions.
  • Figure 14 is an XRPD pattern of different crystalline forms of the right-handed rabeprazole sodium compound in a suspension solution.
  • TGA test Instrument model: Netzsch TG 209F3, temperature range: 25-700 ° C, scanning rate: 20 ° C / min, purge gas: 25 ml / min, protective gas: 15 ml / min
  • Electron microscopy S-3400N, EX-250 electron microscope
  • Mobile phase A 0.025 mol / L phosphate solution (0.025 mol / L dipotassium hydrogen phosphate solution with phosphoric acid to adjust the pH to 7.2) - acetonitrile (95: 5); mobile phase B: methanol; mobile phase C: acetonitrile;
  • Diluent 0.1mol/L dipotassium hydrogen phosphate solution Adjust the pH to 11.3-methanol (45:55) with 2mol/L potassium hydroxide solution.
  • reaction mixture was concentrated to 1/2 volume under reduced pressure at 45 ° C, cooled to 0 to 5 ° C, isopropyl ether 60 ml was added dropwise and stirred for 4 to 5 h. After filtration, the filter cake was evaporated to dryness eluting with 50 ml of isopropyl ether. The moisture was measured to be 4.72%, HPLC 99.91%, and isomer HPLC 100%.
  • the XRPD pattern is shown in Figure 1.
  • the DSC spectrum shown in Figure 2, shows a broad endothermic peak at about 138 ° C and an exothermic peak at about 189 ° C and 226 ° C, respectively.
  • the TGA map is shown in Figure 3.
  • the IR spectrum is shown in Figure 4.
  • the electron microscope scan map is shown in Figure 5.
  • the right-handed rabeprazole wet product was 250 g, and 750 ml of dichloromethane was added and stirred well.
  • the liquid phase was allowed to stand for separation, and the upper aqueous phase was removed and weighed to 88.96 g, and the weight of the right-handed rabeprazole was about 161.04 g.
  • the methylene chloride phase was concentrated to a foamy state under reduced pressure at 30 ° C, and 1200 ml of isopropyl alcohol and 40% aqueous sodium hydroxide (20 g NaOH, 1.1 eq.) were added to the residue, and the reaction was stirred at 35 ° C for 6 h. After the reaction was completed, the reaction was carried out.
  • Example 2 The liquid was concentrated to 1/3 volume under reduced pressure at 45 ° C, cooled to 0 to 5 ° C, 650 ml of isopropyl ether was added dropwise and stirred for 5 h, and the filter cake was rinsed with isopropyl ether 500 ml and dried under reduced pressure to give a white solid 145.12 g.
  • the test pattern is identical to that of Example 1.
  • the reaction solution was concentrated to a volume of 1/2 at 45 ° C under reduced pressure, cooled to 0 to 5 ° C, 150 ml of methyl tert-butyl ether was added dropwise and stirred for 4 to 5 h, and the filter cake was rinsed with methyl tert-butyl ether (80 ml). Dry and dry under reduced pressure to give a white solid.
  • the test pattern is identical to that of Example 1.
  • the XRPD pattern is shown in Figure 6.
  • the DSC spectrum is shown in Figure 7.
  • the TGA map is shown in Figure 8.
  • the IR spectrum is shown in Figure 9.
  • the right-handed rabeprazole sodium crystal was prepared according to the method of Example 1 of CN102924434A, and was designated as Form A.
  • the XRPD pattern is shown in Figure 10 and is consistent with the disclosure of this application.
  • the electron microscope scan is shown in Figure 11.
  • the test results show that the appearance of the four samples is white powder-like; the amorphous form has a lower melting point, the melting range is longer, the thermodynamically unstable state, the melting point of the crystal form is higher, and the melting point of the C crystal form is obvious. It is higher than A crystal form; there is no difference in solubility in water, and it is easy to dissolve; the moisture infiltration at 24h and 48h shows that the amorphous form has the highest wettability, and the A and B crystal forms have the same wettability.
  • the result of the wettability investigation unexpectedly found that the C crystal form has lower wettability than the A crystal form, and because of its extremely low initial moisture (almost anhydrous crystal form C), it has a low moisture content for a long time during storage.
  • the potential advantage of the content Especially in the storage process such as oral tablets and capsules, low moisture content and moisture absorption resistance can often improve the chemical stability of raw materials and auxiliary materials, and effectively reduce the degradation of raw materials due to excessive moisture absorption. At the same time, the product is prevented from being excessively hydrated, and the disintegrating agent is exposed to moisture in the early stage to reduce the disintegration performance in the body.
  • the right-handed rabeprazole sodium A crystal form, B crystal form, and C crystal form were each 100 mg, and the traits and related substances were sampled on the 0th, 10th, 20th, and 30th days under different conditions. The results are shown in Table 4.
  • the test results show that the B crystal form is equivalent to the A crystal form under the conditions of illumination, high temperature and high humidity.
  • the crystal form of C is equivalent to the crystal form of A under illumination conditions; the stability of C crystal form is better than that of A crystal form under high temperature and high humidity conditions.
  • Form C is a stable crystalline form suitable for the preparation of solid preparations such as oral tablets, capsules and the like.
  • Example 8 Difference in fluidity of the right-handed rabeprazole sodium polymorph powder and its effect on the preparation
  • the angle of repose is the key characteristic of the frictional resistance between powder particles. It is an important parameter to characterize the fluidity of powder.
  • Angle of repose determination (A crystal form)
  • Angle of repose determination (B crystal form)
  • the test results show that the value of the angle of repose of the B crystal form is significantly lower than that of the A crystal form. According to the principle and experience of the preparation, when the angle of repose is within 50°, the powder fluidity suitable for the preparation of the preparation can often be exhibited. If the angle of repose is too large, the fluidity of the powder is poor, and the production of the preparation is less. accept.
  • the compression coefficient and its closely related Hausner ratio are simple and fast methods for predicting powder properties, and are often used as indicators for characterizing powder fluidity in production processes.
  • the measurement of the mixing uniformity was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512).
  • Determination method Take about 80.5mg of this product, accurately weighed, set 100ml volumetric flask, add appropriate amount of diluent to dissolve, ultrasonic, dilute to the mark with dilution solution, shake, filter, accurately measure 20 ⁇ l of filtrate, inject into liquid chromatograph, Record the chromatogram; take the appropriate amount of the right-handed rabeprazole sodium reference substance, accurately weigh it, determine it by the same method, and calculate the peak area according to the external standard method.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明提供了右旋雷贝拉唑钠化合物的 B 晶型和 C 晶型。本发明 B 晶型具有良好的稳定性和流动性, C 晶型为无水晶型，具有良好的稳定性和低吸湿性, 适合制备右旋雷贝拉唑钠制剂。

Description

右旋雷贝拉唑钠化合物及其药物组合物 技术领域
本发明属于医药领域，具体涉及右旋雷贝拉唑钠化合物的新晶型及其制备方法，以及含有所述右旋雷贝拉唑钠化合物的药物组合物。
背景技术
右旋雷贝拉唑钠(Dexrabeprazole sodium，式I)，化学名R-(+)-2-{[4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基]甲亚磺酰基}-1H-苯并咪唑钠盐，由印度EMCURE医药公司首家开发，2007年9月在印度上市，用于治疗胃溃疡、十二指肠溃疡、吻合口溃疡、反流性食管炎、卓-艾(Zollinger-Ellison)综合征、(胃泌素瘤)活动性十二指肠溃疡、良性活动性胃溃疡、伴有临床症状的侵蚀性或溃疡性的胃-食管反流证，与适当的抗生素联用可根治幽门螺旋杆菌阳性的十二指肠溃疡。
Figure PCTCN2018092347-appb-000001
CN104910135A公开了一种右旋雷贝拉唑钠的无定形形式，但稳定性差，不适合制备固体制剂。CN102924434A公开了一种右旋雷贝拉唑钠的单水合物晶型，是目前公开的一种较为稳定的晶型。此外没有发现右旋雷贝拉唑钠的其他晶型。为了改进右旋雷贝拉唑钠制剂的质量，进一步研究开发右旋雷贝拉唑钠的优势药物晶型具有重要意义。
发明内容
本发明的目的在于提供式(I)所示的右旋雷贝拉唑钠的新晶型，所述晶型具有良好的稳定性，优良的流动性和低的吸湿性，适于制备药物制剂，尤其是固体制剂。
Figure PCTCN2018092347-appb-000002
一方面，本发明提供一种右旋雷贝拉唑钠化合物的B晶型，其使用Cu靶辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图谱在约6.50±0.2、8.64±0.2、14.46±0.2、15.92±0.2、17.74±0.2、18.40±0.2、19.58±0.2、23.46±0.2度处有特征峰。其中相对强度最大的峰为约23.46±0.2度的特征峰。
进一步地，所述X-射线粉末衍射图谱在约6.50±0.2、8.64±0.2、10.58±0.2、13.14±0.2、14.46±0.2、14.90±0.2、15.48±0.2、15.92±0.2、16.86±0.2、17.74±0.2、18.40±0.2、19.58±0.2、20.34±0.2、21.00±0.2、21.56±0.2、22.44±0.2、22.90±0.2、23.46±0.2、24.04±0.2度处有特征峰。
进一步地，所述右旋雷贝拉唑钠的B晶型具有基本如图1所示的XRPD图。其中2θ角允许有±0.2度的误差。
所述右旋雷贝拉唑钠化合物的B晶型的差示扫描量热(DSC)图谱在约138℃有吸热峰，在约189℃和约226℃有放热峰。其中所述温度允许有±5℃的误差。
所述右旋雷贝拉唑钠化合物的B晶型具有基本如图2所示的DSC图。
所述右旋雷贝拉唑钠化合物的B晶型具有基本如图3所示的热重分析(TGA)图。
所述右旋雷贝拉唑钠化合物的B晶型具有基本如图4所示的红外(IR)图谱。
本发明还提供一种制备式(I)所示的右旋雷贝拉唑钠化合物的B晶型的方法，包括：
1)将右旋雷贝拉唑加入有机溶剂中，搅拌，分出有机层，浓缩至干；
2)向残余物中加入醇溶剂和氢氧化钠水溶液，搅拌反应；
3)反应完成后，向反应液滴加反溶剂析晶，即得。
所述步骤1)的有机溶剂选自二氯甲烷、三氯甲烷和乙酸乙酯，优选二氯甲烷。
所述步骤2)的醇溶剂选自异丙醇、正丙醇和正丁醇，优选异丙醇。
所述步骤3)的反溶剂选自异丙醚、甲基叔丁醚、二乙醚和甲基乙基醚，优选异丙醚。
在优选的实施方式中，步骤1)中右旋雷贝拉唑与有机溶剂的比例可以是1g:(1～10)ml，如1g:(3～5)ml。
在优选的实施方式中，右旋雷贝拉唑与步骤2)中醇溶剂的比可以是1g:(1～10)ml，如1g:(3～5)ml。
在优选的实施方式中，步骤2)中氢氧化钠水溶液浓度为40％wt。
在优选的实施方式中，步骤3)的反溶剂用量为反应液体积的1～5倍，如2～3倍。
在优选的实施方式中，步骤3)的反应完成后，可将反应液先浓缩减小体积，然后滴加反溶剂。浓缩是使溶液缩小至任意部分体积，例如1/2体积、1/3体积、1/4体积、1/5体积等。反应液浓缩后滴加反溶剂析晶，可以相应地减少反溶剂的用量，加快析晶过程。浓缩可在35～45℃进行。
在优选的实施方式中，步骤3)中滴加反溶剂可以在低温条件下进行，低温可以是10℃以下。例如将反应液冷却至0～10℃，优选0～5℃，滴加反溶剂析晶。
另一方面，本发明提供一种右旋雷贝拉唑钠化合物的C晶型，其使用Cu靶辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图谱在约6.22±0.2、12.14±0.2、12.46±0.2、15.82±0.2、18.90±0.2、22.38±0.2、26.56±0.2、28.06±0.2度处有特征峰。其中相对强度最大的峰为约6.22±0.2度的特征峰。
进一步地，所述X-射线粉末衍射图谱在约6.22±0.2、12.14±0.2、12.46±0.2、13.10±0.2、 15.82±0.2、17.34±0.2、17.70±0.2、18.90±0.2、20.18±0.2、20.74±0.2、21.60±0.2、22.08±0.2、22.38±0.2、23.42±0.2、26.56±0.2、28.06±0.2、30.80±0.2度处有特征峰。
进一步地，所述右旋雷贝拉唑钠化合物的C晶型具有基本如图6所示的XRPD图。其中2θ角允许有±0.2度的误差。
所述右旋雷贝拉唑钠化合物的C晶型的差示扫描量热(DSC)图谱在在约234℃有放热峰。其中所述温度允许有±5℃的误差。
所述右旋雷贝拉唑钠化合物的C晶型具有基本如图7所示的DSC图。
所述右旋雷贝拉唑钠化合物的C晶型具有基本如图8所示的TGA图。
所述右旋雷贝拉唑钠化合物的C晶型具有基本如图9所示的IR图。
本发明还提供一种制备式(I)所示的右旋雷贝拉唑钠化合物的C晶型的方法，包括步骤：
1)将右旋雷贝拉唑钠溶于甲醇或乙醇中，减压浓缩至干，重复前述操作至少1次；
2)向步骤1)所得的残余物加入乙腈，搅拌，减压浓缩至干；
3)向步骤2)所得的残余物加入溶剂甲苯或二甲苯，搅拌析晶，得C晶型。
在优选的实施方式中，所述步骤1)中将右旋雷贝拉唑钠溶于甲醇。
在优选的实施方式中，所述步骤1)的溶解和浓缩操作的重复次数优选为1-6次，更优选2-5次，例如3-4次。
在优选的实施方式中，步骤3)的搅拌析晶在惰性气体保护下进行，例如氮气。
在优选的实施方式中，步骤1)中右旋雷贝拉唑钠与有机溶剂的比例可以是1g:(1-20)ml，如1g:(3-10)ml。
在优选的实施方式中，右旋雷贝拉唑钠与步骤2)中乙腈的比例可以是1g:(1-20)ml，如1g:(3-10)ml。
在优选的实施方式中，右旋雷贝拉唑钠与步骤3)中溶剂的比例可以是1g:(5-30)ml。
本发明还提供一种药物组合物，其含有上述晶型的右旋雷贝拉唑钠化合物以及药学上可接受的载体。所述药物组合物可以制成任意剂型，优选口服制剂，例如肠溶片剂、胶囊等，或者注射制剂，如冻干粉针剂。
本发明还提供上述右旋雷贝拉唑钠化合物或其药物组合物在制备用于治疗或预防胃肠疾病中的用途。例如，胃溃疡、十二指肠溃疡、吻合口溃疡、反流性食管炎、卓-艾(Zollinger-Ellison)综合征(胃泌素瘤)、活动性十二指肠溃疡、良性活动性胃溃疡、伴有临床症状的侵蚀性或溃疡性的胃-食管反流证，与适当的抗生素联用可根治幽门螺旋杆菌阳性的十二指肠溃疡。
本发明的右旋雷贝拉唑钠的B晶型表现出良好的稳定性，并具有良好的流动性，尤其适于制备口服制剂，可以改善制剂的均一性和质量稳定性。本发明的右旋雷贝拉唑钠C晶型为无水晶型，水分含量低且不易吸潮，具有优良的稳定性，适于制备药物制剂。
附图说明
图1是右旋雷贝拉唑钠化合物的B晶型的XRPD图。
图2是右旋雷贝拉唑钠化合物的B晶型的DSC图。
图3是右旋雷贝拉唑钠化合物的B晶型的TGA图。
图4是右旋雷贝拉唑钠化合物的B晶型的IR图。
图5是右旋雷贝拉唑钠化合物的B晶型的电镜扫描图。
图6是右旋雷贝拉唑钠化合物的C晶型的XRPD图。
图7是右旋雷贝拉唑钠化合物的C晶型的DSC图。
图8是右旋雷贝拉唑钠化合物的C晶型的TGA图。
图9是右旋雷贝拉唑钠化合物的C晶型的IR图。
图10是右旋雷贝拉唑钠化合物的A晶型的XRPD图。
图11是右旋雷贝拉唑钠化合物的A晶型的电镜扫描图。
图12是右旋雷贝拉唑钠化合物的无定形物态的XRPD图。
图13是右旋雷贝拉唑钠化合物的不同晶型在研磨/高温条件下的XRPD图。
图14是右旋雷贝拉唑钠化合物的不同晶型在混悬溶液中的XRPD图。
具体实施方式
以下通过具体实施例详细说明本发明，然而本领域技术人员可以理解，下述实施例仅是解释说明的目的，而不以任何方式限制本发明的范围。如无特别说明，实施例中的操作步骤均为常规操作。
测试方法：
XRPD测试(图1、6，南京师范大学分析测试中心)：仪器型号D/max 2500VL/PC，靶型：Cu(60kV，100mA)，扫描范围：3°-40°(2theta值)，扫描步长：0.02，扫描速度：5
DSC测试：仪器型号：Perkin Elmer DSC 8500，温度范围：50-300℃，扫描速率：10℃/min，氮气流速：50ml/min
TGA测试：仪器型号：Netzsch TG 209F3，温度范围：25-700℃，扫描速率：20℃/min，吹扫气：25ml/min，保护气：15ml/min
IR测试：Thermo公司，仪器型号：NICOLET is5红外色谱仪，扫描次数：32，分辨率：4.000，采样增益：1.0，动静速度：0.4747，光阑：100.00，检测器DTGS KBr，分束器：KBr，光源：红外光源
XRPD测试(图10、12-14，南京大学现代分析中心)：仪器型号：Thermo公司X’TRA型X衍射仪，靶型：Cu(40kV，40mA)，扫描范围：2°-40°(2theta值)，扫描步长：0.02，扫描速度：5
电镜扫描：S-3400N、EX-250电子显微镜
休止角测定：BT-1001智能粉体特性测试仪(丹东百特仪器有限公司)
引湿水分测定：25±1℃恒温干燥器(底部放氯化铵饱和溶液)
有关物质色谱条件：
色谱柱：用十八烷基硅烷键合硅胶为填充剂(Agilent ZORBAX Extend C18,250×4.6mm,5μm)；
流动相A：0.025mol/L磷酸盐溶液(0.025mol/L磷酸氢二钾溶液用磷酸调节pH值至7.2)-乙腈(95:5)；流动相B：甲醇；流动相C：乙腈；
按下表进行线性梯度洗脱：
时间(min) A(％) B(％) C(％)
0 65 30 5
15 65 30 5
45 15 55 30
50 15 55 30
52 65 30 5
60 65 30 5
检测波长：280nm、220nm(用于杂质H)
流速：1.0ml/min
柱温：25℃
进样量：5μl
稀释液：0.1mol/L磷酸氢二钾溶液用2mol/L氢氧化钾溶液调节pH至11.3-甲醇(45:55)
左旋异构体检测色谱条件：
色谱柱：Chiralpack AGP手性色谱柱(150mm×4.0mm，5μm)
流动相：0.01mol/L磷酸盐溶液(0.01mol/L磷酸氢二钾溶液用磷酸调节pH至6.8，即得)-乙腈(90:10)
稀释液：0.05mol/L氢氧化钠溶液-甲醇(40:60)
检测波长：290nm
流速：0.8ml/min
柱温：30℃
进样量：10μl
实施例1右旋雷贝拉唑钠的B晶型的制备
取右旋雷贝拉唑湿品25.12g，加入二氯甲烷75ml充分搅拌，静置分液，将上层水相去除称重8.98g，得右旋雷贝拉唑重量约为16.14g。将二氯甲烷相在30℃减压浓缩至褐色泡沫状，向残余物加入异丙醇120ml和40％氢氧化钠水溶液(1.98gNaOH，1.1当量)，35℃搅拌反应5～6h。反应完成后，向反应液加入1ml纯化水并氮气保护搅拌96h，将反应液于45℃ 减压浓缩至1/2体积，冷却至0～5℃，滴加异丙醚60ml并搅拌4～5h过滤，滤饼用异丙醚50ml淋洗抽干，减压干燥得白色固体14.37g。测得水分4.72％，HPLC 99.91％，异构体HPLC100％。
XRPD图谱如图1所示。DSC图谱如图2所示，显示在约138℃有一宽的吸热峰，在约189℃和226℃分别有放热峰。TGA图谱如图3所示。IR图谱如图4所示。电镜扫描图谱如图5所示。
表1.右旋雷贝拉唑钠的B晶型的XRPD图谱数据
序号 2θ d值 相对强度 序号 2θ d值 相对强度
1 6.50 13.587 75 12 19.58 4.530 65
2 8.64 10.226 37 13 20.34 4.362 30
3 10.58 8.355 15 14 21.00 4.227 27
4 13.14 6.732 15 15 21.56 4.118 28
5 14.46 6.12 24 16 22.44 3.959 32
6 14.90 5.941 18 17 22.90 3.880 29
7 15.48 5.719 20 18 23.46 3.789 100
8 15.92 5.562 25 19 24.04 3.699 29
9 16.86 5.254 23 20 24.54 3.625 29
10 17.74 4.996 63 21 26.42 3.371 31
11 18.40 4.818 63 22 28.52 3.127 20
实施例2右旋雷贝拉唑钠的B晶型的制备
取右旋雷贝拉唑湿品250g，加入二氯甲烷750ml充分搅拌，静置分液，将上层水相去除称重88.96g，得右旋雷贝拉唑重量约为161.04g。将二氯甲烷相在30℃减压浓缩至泡沫状，向残余物加入异丙醇1200ml和40％氢氧化钠水溶液(20g NaOH，1.1当量)，35℃搅拌反应6h，反应完成后，将反应液于45℃减压浓缩至1/3体积，冷却至0～5℃，滴加异丙醚620ml并搅拌5h过滤，滤饼用异丙醚500ml淋洗抽干，减压干燥得白色固体145.12g。测试图谱与实施例1一致。
实施例3右旋雷贝拉唑钠的B晶型的制备
取右旋雷贝拉唑湿品50.55g，加入三氯甲烷150ml充分搅拌，静置分液，将上层水相去除称重18.65g，得右旋雷贝拉唑重量约为31.90g。将三氯甲烷相在30℃减压浓缩至泡沫状，向残余物加入异丙醇240ml和40％氢氧化钠水溶液(4.0g NaOH，1.1当量)，35℃搅拌反应5～6h，反应完成后，将反应液于45℃减压浓缩至1/2体积，冷却至0～5℃，滴加甲基叔丁醚150ml并搅拌4～5h过滤，滤饼用甲基叔丁醚80ml淋洗抽干，减压干燥得白色固 体28.38g。测试图谱与实施例1一致。
实施例4：右旋雷贝拉唑钠的C晶型的制备
取右旋雷贝拉唑钠10g，加入50ml甲醇搅拌溶解，于45℃减压浓缩至干，呈泡沫状，重复上述浓缩步骤5次，残余物加入乙腈50ml约20-35℃搅拌结晶18-24h，将反应液T＝45℃减压浓缩，向残余物加入甲苯150ml，氮气保护下于35℃搅拌结晶24h，过滤，滤饼用甲苯50ml淋洗抽干，40℃减压干燥24h得白色固体9.5g。有关物质HPLC：99.92％，单杂0.028％，水分KF 0.11％；异构体HPLC：100％。
XRPD图谱如图6所示。DSC图谱如图7所示。TGA图谱如图8所示。IR图谱如图9所示。
表2.右旋雷贝拉唑钠的C晶型的XRPD图谱数据
序号 2θ d值 相对强度 序号 2θ d值 相对强度
1 6.22 14.198 100 10 20.74 4.279 13
2 12.14 7.284 19 11 21.60 4.111 16
3 12.46 7.098 13 12 22.08 4.022 19
4 13.10 6.753 11 13 22.38 3.969 27
5 15.82 5.597 40 14 23.42 3.795 17
6 17.34 5.110 19 15 26.56 3.353 27
7 17.70 5.007 13 16 28.06 3.177 20
8 18.90 4.691 20 17 30.80 2.901 13
9 20.18 4.397 14 - - - -
实施例5：右旋雷贝拉唑钠的C晶型的制备
取右旋雷贝拉唑钠20g，加入100ml甲醇搅拌溶解，于45℃减压浓缩至干，呈泡沫状，重复上述浓缩步骤4次，残余物加入乙腈100ml约25℃搅拌结晶20h，将反应液45℃减压浓缩，向残余物加入甲苯300ml，氮气保护下于35℃搅拌结晶24h，过滤，滤饼用甲苯90ml淋洗抽干，40℃减压干燥24h得白色固体18.9g。测试图谱与实施例1基本一致。
实施例6右旋雷贝拉唑钠多晶型的理化性质研究
按照CN102924434A说明书实施例1的方法制备右旋雷贝拉唑钠晶体，记为A晶型。XRPD图谱如图10所示，与该申请公开的一致。电镜扫描图如图11所示。
将右旋雷贝拉唑100g溶解于300ml二氯甲烷中，分去上层水层，有机层缓缓加入异丙醚2L，室温搅拌1h过滤，滤饼用异丙醚500ml淋洗、抽干、35℃减压干燥12h得右旋雷贝拉唑钠固体63.5g，为无定形态。XRPD图谱如图12所示。
将上述右旋雷贝拉唑钠无定形态、A晶型、B晶型、C晶型分别取样，检测理化性质，结果见表3。
表3.右旋雷贝拉唑钠多晶型的理化性质研究
Figure PCTCN2018092347-appb-000003
试验结果显示：四种样品的外观性状均为类白色粉末状；无定形态熔点较低，熔程较长，处于热力学不稳定状态，晶型的熔点均较高，且C晶型的熔点明显高于A晶型；在水中溶解度基本没有差异，均为易溶解；24h、48h引湿水分考察显示，无定形态引湿性最高，A、B晶型引湿性相当。引湿性考察结果意外发现，C晶型引湿性低于A晶型，且由于其极低的初始水分(几乎无水的晶型C)，使其具有存贮过程中可以长时间保持较低水分含量的潜在优势。尤其在诸如口服片剂、胶囊剂的存储过程中，低水分含量及抗吸湿性常常能够提升原料和辅料的化学稳定性，有效降低产品因吸湿水分过高产生的原辅料降解副反应。同时避免产品因水分过大，崩解剂前期接触水分而降低体内的崩解性能。
实施例7右旋雷贝拉唑钠多晶型的稳定性研究
7.1影响因素试验
取右旋雷贝拉唑钠A晶型、B晶型、C晶型各100mg，置于不同条件下，分别于第0、10、20、30天取样检测性状及有关物质。结果如表4所示。
表4.右旋雷贝拉唑钠多晶型的稳定性研究
Figure PCTCN2018092347-appb-000004
Figure PCTCN2018092347-appb-000005
试验结果显示，在光照、高温、高湿条件下B晶型与A晶型稳定性相当。在光照条件下C晶型与A晶型稳定性相当；高温高湿条件下C晶型的稳定性优于A晶型。
7.2高温试验
取右旋雷贝拉唑钠A晶型、C晶型按下表5所示置于不同条件下，取样进行XRPD检测，考 察晶型变化。XRPD拟合图如图13所示。
表5.右旋雷贝拉唑钠多晶型在高温条件下的稳定性研究
Figure PCTCN2018092347-appb-000006
试验结果显示，晶型C在高温下保持稳定，不会发生转晶；A晶型在高温下不稳定，容易发生转晶，出现晶型C的特征峰，判断其高温条件下转变为C晶型；A晶型在研磨时候转化为部分无定型态。因此C晶型是稳定的晶型，适合制备固体制剂，如口服片剂、胶囊等。
7.3混悬平衡试验
按下表组别，将无定型态、A晶型和C晶型样品各取1g混合，在35℃及氮气氛围条件下与10ml溶剂搅拌，取样进行XRPD检测，图谱如图14所示。试验条件及结果如下表6所示。
表6.右旋雷贝拉唑钠多晶型的混悬平衡
组别 起始样品混合物 混悬溶剂 混悬时间(天) 产物晶型
G-1 C晶型+无定型 乙腈 2 C晶型
G-2 A晶型+C晶型 乙腈 2 C晶型
G-3 A晶型+无定型 乙腈 2 C晶型
结果显示，右旋雷贝拉唑钠C晶型的稳定性优于无定形态和A晶型，是非常稳定的晶型。
实施例8右旋雷贝拉唑钠多晶型粉体流动性差异及对制剂的影响
8.1流动性
休止角是粉体颗粒间摩擦阻力的关键特性，是表征粉体流动性的重要参数，休止角测定方法是测量粉体堆积所成的圆锥高度和基底半径，计算公式：tan(α)＝高度/半径。分别取A晶型和B晶型测试休止角比较差异。结果如下表7所示。
表7.右旋雷贝拉唑钠A晶型和B晶型的休止角数据
休止角测定(A晶型) 休止角测定(B晶型)
1st58.93° 1st36.35°
2nd58.86° 2nd36.35°
3rd58.88° 3rd36.34°
平均值：58.89° 平均值：36.35°
试验结果显示，B晶型的休止角数值明显低于A晶型。根据制剂原理及经验，当休止角在50°以内时常常能够表现出适合制剂生产的粉体流动性，若休止角过大，则预示粉体流动性较差，对制剂生产来讲较少被接受。
压缩系数及其密切相关的Hausner比是预测粉体特性简单快速的方法，常在生产工艺上被作为表征粉末流动性的指标。
分别取A晶型和B晶型测定不同晶型粉体振实密度和松密度并计算压缩系数和Hausner比值。结果如下表8所示。其中：压缩系数(％)＝[(振实密度-松密度)/振实密度×100％；Hausner比值＝振实密度/松密度。
表8.右旋雷贝拉唑钠多晶型的流动性数据
  A晶型 B晶型
振实密度(g.cm -3) 0.450 0.515
松密度(g.cm -3) 0.267 0.398
压缩系数 40.67％ 22.72％
Hausner比 1.69 1.29
试验结果显示，B晶型的压缩系数和Hausner数值明显优于A晶型。A晶型压缩系数大于38％及Hausner比大于1.60的数值显示其固体形态较差的粉体流动性。
8.2混合均匀度
制剂处方：
Figure PCTCN2018092347-appb-000007
制剂工艺：
1)分别取处方量的右旋雷贝拉唑钠、淀粉、预胶化淀粉、微晶纤维素、羟丙甲基纤维素、氧化镁充分混匀；
2)向上述混合物中加入处方量的PVPK30制湿粒(18目筛)，50℃干燥约1-2小时，16目筛整粒，外加硬脂酸镁，分别在加入第10、15、20min用取样工具混合物样品进行均匀度考察，结果如表9和表10所示。
混合均匀度测定照高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂；以0.05mol/L磷酸盐溶液(0.05mol/L磷酸氢二钠溶液用0.05mol/L磷酸二氢钾溶液调节pH值至7.0，即得)-甲醇(45:55)为流动相；检测波长为290nm。理论板数按右旋雷贝拉唑钠峰计算应不低于2000。
测定法取本品约80.5mg，精密称定，置100ml量瓶，加适量稀释液溶解，超声，用稀释液稀释至刻度，摇匀，过滤，精密量取滤液20μl，注入液相色谱仪，记录色谱图；另取右旋雷贝拉唑钠对照品适量，精密称定，同法测定，按外标法以峰面积计算，即得。
稀释液：0.05mol/L氢氧化钠溶液-甲醇(40:60)
仪器：LC-20高效液相色谱仪 日本岛津
XS205电子分析天平 梅特勒
SevenMulti S40pH计 梅特勒
表9.A晶型混合物的均匀度(w/w，％)
Figure PCTCN2018092347-appb-000008
表10.B晶型混合物的均匀度(w/w，％)
Figure PCTCN2018092347-appb-000009
结果及分析：右旋雷贝拉唑钠B晶型处方原辅料混合均匀度明显优于A晶型。在制剂领域，原料药与辅料的混合是片剂生产的关键步骤，原辅料混合均匀是直接影响片剂含量、重量差异稳定均一的重要参数，由于B晶型具有良好的粉体流动性，原辅料混合15min时，RSD已低于2％，符合指标要求，其更适用于制备右旋雷贝拉唑钠的固体制剂。

Claims (10)

  1. 一种如式(I)所示的右旋雷贝拉唑钠化合物，
    Figure PCTCN2018092347-appb-100001
    其特征在于，所述右旋雷贝拉唑钠化合物为B晶型，其使用Cu靶辐射，以2θ角度表示的XRPD图谱在约6.50±0.2、8.64±0.2、14.46±0.2、15.92±0.2、17.74±0.2、18.40±0.2、19.58±0.2、23.46±0.2度处有特征峰。
  2. 如权利要求1所述的右旋雷贝拉唑钠化合物，其特征在于，所述右旋雷贝拉唑钠化合物包括如下一个或多个特征：
    1)具有的XRPD图谱在约6.50±0.2、8.64±0.2、10.58±0.2、13.14±0.2、14.46±0.2、14.90±0.2、15.48±0.2、15.92±0.2、16.86±0.2、17.74±0.2、18.40±0.2、19.58±0.2、20.34±0.2、21.00±0.2、21.56±0.2、22.44±0.2、22.90±0.2、23.46±0.2、24.04±0.2度处有特征峰；
    2)具有基本如图1所示的XRPD图；
    3)具有的DSC图在约138±5℃有吸热峰，在约189±5℃和约226±5℃有放热峰；
    4)具有基本如图2所示的DSC图；
    5)具有基本如图3所示的TGA图；
    6)具有基本如图4所示的IR图谱。
  3. 一种制备权利要求1或2所述的右旋雷贝拉唑钠化合物的方法，包括步骤：
    1)将右旋雷贝拉唑加入有机溶剂中，搅拌，分出有机层，浓缩至干；
    2)向残余物中加入醇溶剂和氢氧化钠水溶液，搅拌反应；
    3)反应完成后，向反应液滴加反溶剂析晶，即得。
  4. 如权利要求3所述的方法，包括下述特征a)～e)的一个或多个：
    a)其中步骤1)的有机溶剂选自二氯甲烷、三氯甲烷和乙酸乙酯；
    b)其中步骤2)的醇溶剂选自异丙醇、正丙醇和正丁醇；
    c)其中步骤3)的反溶剂选自异丙醚、甲基叔丁醚、二乙醚和甲基乙基醚；
    d)其中步骤3)中反应完成后，将反应液先浓缩减小体积，然后滴加反溶剂；
    e)其中步骤3)中滴加反溶剂是在低温条件下进行。
  5. 一种如式(I)所示的右旋雷贝拉唑钠化合物，其特征在于，所述右旋雷贝拉唑钠化合物为C晶型，其使用Cu靶辐射，以2θ角度表示的XRPD图谱在6.22±0.2、12.14±0.2、12.46±0.2、15.82±0.2、18.90±0.2、22.38±0.2、26.56±0.2、28.06±0.2度处有特征峰。
  6. 如权利要求5所述的右旋雷贝拉唑钠化合物，其特征在于，所述右旋雷贝拉唑钠化合物包括如下一个或多个特征：
    1)具有的XRPD图谱在6.22±0.2、12.14±0.2、12.46±0.2、13.10±0.2、15.82±0.2、17.34±0.2、 17.70±0.2、18.90±0.2、20.18±0.2、20.74±0.2、21.60±0.2、22.08±0.2、22.38±0.2、23.42±0.2、26.56±0.2、28.06±0.2、30.80±0.2度处有特征峰；
    2)具有基本如图6所示的XRPD图谱；
    3)具有的DSC图谱在约234℃±5℃有放热峰；
    4)具有基本如图7所示的DSC图谱；
    5)具有基本如图8所示的TGA图谱；
    6)具有基本如图9所示的IR图谱。
  7. 一种制备权利要求5或6所述的右旋雷贝拉唑钠化合物的方法，包括步骤：
    1)将右旋雷贝拉唑钠溶于甲醇或乙醇中，减压浓缩至干，重复操作该步骤至少1次；
    2)向步骤1)所得的残余物加入乙腈，搅拌，减压浓缩至干；
    3)向步骤2)所得的残余物加入溶剂甲苯或二甲苯，搅拌析晶，即得。
  8. 如权利要求7所述的方法，包括下述特征a)～c)的一个或多个：
    a)其中步骤1)右旋雷贝拉唑钠溶于甲醇；
    b)其中步骤1)的重复操作次数优选为1-6次；
    c)其中步骤3)的搅拌析晶在惰性气体保护下进行。
  9. 一种药物组合物，包含权利要求1或5任一项所述的右旋雷贝拉唑钠化合物以及药物学上可接受的载体。
  10. 权利要求9所述的药物组合物在制备用于治疗或预防胃肠疾病中的用途。
PCT/CN2018/092347 2017-06-23 2018-06-22 右旋雷贝拉唑钠化合物及其药物组合物 Ceased WO2018233678A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/624,740 US11078184B2 (en) 2017-06-23 2018-06-22 Dexrabeprazole sodium compound and pharmaceutical composition thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710485939.5A CN109111428A (zh) 2017-06-23 2017-06-23 一种右旋雷贝拉唑钠化合物及其药物组合物
CN201710487802.3 2017-06-23
CN201710485939.5 2017-06-23
CN201710487802.3A CN109111429A (zh) 2017-06-23 2017-06-23 右旋雷贝拉唑钠化合物及其药物组合物

Publications (1)

Publication Number Publication Date
WO2018233678A1 true WO2018233678A1 (zh) 2018-12-27

Family

ID=64735506

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/092347 Ceased WO2018233678A1 (zh) 2017-06-23 2018-06-22 右旋雷贝拉唑钠化合物及其药物组合物

Country Status (2)

Country Link
US (1) US11078184B2 (zh)
WO (1) WO2018233678A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118010878A (zh) * 2021-03-01 2024-05-10 丽珠集团丽珠制药厂 一种雷贝拉唑钠肠溶制剂中杂质的测定方法与应用
CN114609268B (zh) * 2022-02-10 2024-04-16 南京海纳医药科技股份有限公司 一种右旋雷贝拉唑钠原料药中有关物质的检测方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924434A (zh) * 2012-10-18 2013-02-13 江苏诚信制药有限公司 一种右旋雷贝拉唑钠单水合物晶型及其制备方法
CN104031030A (zh) * 2014-04-21 2014-09-10 海南海力制药有限公司 一种右旋雷贝拉唑钠单水合物晶型及其制备方法
CN104725358A (zh) * 2013-12-23 2015-06-24 江苏神龙药业有限公司 一种右旋雷贝拉唑钠水合物的新晶型及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104910135A (zh) 2014-03-11 2015-09-16 南京柯菲平盛辉制药有限公司 右旋雷贝拉唑钠新晶型的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924434A (zh) * 2012-10-18 2013-02-13 江苏诚信制药有限公司 一种右旋雷贝拉唑钠单水合物晶型及其制备方法
CN104725358A (zh) * 2013-12-23 2015-06-24 江苏神龙药业有限公司 一种右旋雷贝拉唑钠水合物的新晶型及其制备方法
CN104031030A (zh) * 2014-04-21 2014-09-10 海南海力制药有限公司 一种右旋雷贝拉唑钠单水合物晶型及其制备方法

Also Published As

Publication number Publication date
US11078184B2 (en) 2021-08-03
US20200216414A1 (en) 2020-07-09

Similar Documents

Publication Publication Date Title
CN108864077B (zh) 小檗碱有机酸盐的固体形式及其制备方法
US9505744B2 (en) Solid state forms of vilazodone and vilazodone hydrochloride
CN113795490A (zh) N-(3-(2-(2-羟基乙氧基)-6-吗啉代吡啶-4-基)-4-甲基苯基)-2(三氟甲基)异烟酰胺的新结晶形式作为Raf抑制剂治疗癌症
WO2011095059A1 (zh) 达沙替尼多晶型物及其制备方法和药物组合物
RU2704795C2 (ru) Кристаллическая форма бисульфата ингибитора jak и способ ее получения
CN115433246B (zh) 葡萄糖胺衍生物的晶型、制备方法及用途
US11117875B2 (en) Crystalline forms, preparation methods and pharmaceutical compositions of ozanimod
EP3555061A1 (en) Solid state forms of apalutamide
US20210332014A1 (en) Cabozantinib malate crystal form, preparation method and use thereof
WO2018184185A1 (zh) 奥扎莫德加成盐晶型、制备方法及药物组合物和用途
WO2021129589A1 (zh) Kd-025的新晶型及其制备方法
CN117263849A (zh) 一种雷芬那辛三水合物晶型及其制备方法
WO2018233678A1 (zh) 右旋雷贝拉唑钠化合物及其药物组合物
JP2023512621A (ja) フルバチニブ又はそのメタンスルホン酸塩の結晶形およびその製造方法
CN111712486B (zh) 卡利拉嗪盐酸盐的晶型及其制备方法及其用途
WO2015003571A1 (zh) 达拉菲尼甲磺酸盐的新晶型及其制备方法
TWI724651B (zh) 貝前列素-314d單水合物晶體及其製備方法
WO2018137670A1 (zh) 一种病毒蛋白抑制剂药物vx-787的晶型及其制备方法和用途
WO2019134455A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2022171117A1 (zh) 含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途
JP2024515770A (ja) タファミジスの固体形態及びその製造方法
CN109111429A (zh) 右旋雷贝拉唑钠化合物及其药物组合物
CN114341113A (zh) 乙酰化艾曲波帕的新晶型及其制备方法
US7777049B2 (en) Crystalline forms of Rizatriptan benzoate
AU2020378025A1 (en) Crystal form of Aprocitentan, preparation method therefor and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18821180

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18821180

Country of ref document: EP

Kind code of ref document: A1