WO2022083476A1 - Gefapixant柠檬酸盐的晶型及其制备方法和用途 - Google Patents

Gefapixant柠檬酸盐的晶型及其制备方法和用途 Download PDF

Info

Publication number
WO2022083476A1
WO2022083476A1 PCT/CN2021/123311 CN2021123311W WO2022083476A1 WO 2022083476 A1 WO2022083476 A1 WO 2022083476A1 CN 2021123311 W CN2021123311 W CN 2021123311W WO 2022083476 A1 WO2022083476 A1 WO 2022083476A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
csi
citrate
form csi
compound
Prior art date
Application number
PCT/CN2021/123311
Other languages
English (en)
French (fr)
Inventor
陈敏华
朱宏艳
Original Assignee
苏州科睿思制药有限公司
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
Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Publication of WO2022083476A1 publication Critical patent/WO2022083476A1/zh

Links

Images

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Gefapixant citrate and its preparation method and use.
  • Chronic cough is a cough that persists for more than eight weeks and can be caused by lung disease (eg, asthma, chronic obstructive pulmonary disease, or idiopathic pulmonary fibrosis), extrapulmonary disease (allergic rhinitis, gastroesophageal reflux), certain A side effect of the drug, or an unrecognized cause.
  • Chronic cough is characterized by high frequency of coughs (10-100 per hour) and long duration (months or years).
  • the P2X3 receptor is an adenosine triphosphate (ATP)-gated ion channel expressed by sensory neurons and is a target for the treatment of chronic sensitization disorders.
  • P2X3 receptors play a key role in the sensitization of certain sensory nerves. Triggered by injury or infection in the airways and lungs, these sensory nerves are activated or sensitized in pathological conditions mediated by common cellular signaling (ATP), resulting in excessive, persistent, and frequent cough urges, known as chronic cough.
  • ATP common cellular signaling
  • Gefapixant is the first non-narcotic P2X3 receptor blocker that selectively blocks ATP activation of P2X3 receptors and is potentially useful for the treatment of cough, chronic cough and cough in respiratory conditions and disorders, among other conditions impulse.
  • Compound I 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • WO2019209607A1 discloses Compound I citrate methanol solvate crystal form 1, isopropanol solvate crystal form 1 and hydrated methanol solvate crystal form 1.
  • WO2019209607A1 also discloses that Compound I citrate can form a solvate with ethanol/water, isopropanol/water, tetrahydrofuran or N-methylpyrrolidone.
  • Q3C Impurities: Guidelines for Residual Solvents" issued by ICH, methanol, tetrahydrofuran and N-methylpyrrolidone belong to class 2 solvents.
  • Class 2 solvents are solvents that are carcinogenic to animals and need to be strictly restricted in pharmaceutical products to protect patients protected from potential adverse reactions.
  • ethanol is metabolized by the liver to acetaldehyde.
  • acetaldehyde is a class 1 carcinogen.
  • Isopropyl alcohol is a potent central nervous system depressant, and poisoning by ingestion or inhalation may cause coma and respiratory arrest. Its metabolite is acetone, which may cause and prolong central nervous system depression.
  • the compound I citrate solvate disclosed in WO2019209607A1 is not suitable for drug development, and to a certain extent, it shows that the compound I citrate solvate is easy to obtain solvate.
  • WO2018118668A1 discloses Compound I citrate crystal form A and crystal form B, and its specification also discloses "It is speculated that crystal form A may be the most thermodynamically stable anhydrous form of citrate".
  • NMR data showed that both Form A and Form B had solvent residues. Residual solvents may lead to drug transcrystallization or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects. In addition, the residual solvent itself can also affect the safety of the drug.
  • Compound I citrate easily forms a solvate, and it is very difficult to obtain a new crystal form that meets the pharmaceutical standards.
  • the inventors of the present application have found that, in addition to the solvate disclosed in the WO2019209607A1 patent, Compound I citrate can also interact with various other solvents (2-methyltetrahydrofuran, trifluoroethanol, dibromomethane, p-xylene, benzoyl ether, n-butanol, toluene, etc.) form solvates or hydrated solvates.
  • the inventors of the present application tried a variety of experimental methods (such as volatilization, cooling, humidity induction, anti-solvent addition, gas-liquid diffusion and gas-solid diffusion, etc.), and carried out more than 1,000 experiments, but no new crystal forms that meet the pharmaceutical standards have been obtained. .
  • the experimental method of volatilization is very easy to obtain the amorphous form of Compound I citrate, even if the inventor of the present application has conducted a large number of experimental studies, including trying a variety of single or mixed solvents, changing the initial concentration of volatilization, the mixing ratio of solvents and It is also difficult to obtain a new crystal form that meets the pharmaceutical standards by changing the volume of the volatilized solution and the temperature of volatilization.
  • the crystal form CSI of the present invention was finally found creatively. It has advantages in at least one aspect of dissolution residue, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc., especially without dissolution residue, solubility, etc. High, solves the problems existing in the prior art, and has very important significance for the development of drugs containing compound I.
  • the present invention provides a new crystal form of compound I citrate, a preparation method and use of the new crystal form, and a pharmaceutical composition thereof.
  • the present invention provides Compound I citrate crystal form CSI (hereinafter referred to as "crystal form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI is characterized at any one of the diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 18.5° ⁇ 0.2° peaks; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at 3 positions in the diffraction angle 2 ⁇ of 10.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 18.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has features at any one of the diffraction angle 2 ⁇ values of 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 24.7° ⁇ 0.2° peaks; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at 3 positions in the diffraction angle 2 ⁇ of 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 24.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 11.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, 10.5° ⁇ 0.2° , 13.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, 18.0° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 16.7° ⁇ 0.2°, 22.6° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 1 .
  • differential scanning calorimetry analysis diagram of the crystalline form CSI is basically shown in FIG. 2 .
  • thermogravimetric analysis diagram of the crystalline form CSI is basically as shown in FIG. 3 , heating to 100° C. has a mass loss of about 3.5%, corresponding to the desorption of water.
  • the crystal form CSI is a hydrate crystal form.
  • the present invention also provides a preparation method of crystal form CSI, characterized in that the preparation method comprises: dissolving the solid compound I citrate in a mixed solvent of water and alcohols, and slowly volatilizing to obtain crystal form CSI .
  • the alcohols are preferably trifluoroethanol; the temperature of the slow volatilization is preferably 2-40° C.; the ratio of the mixed solvent (water:alcohols, v:v) is 1:25-1:2.
  • the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline form CSI and pharmaceutically acceptable excipients.
  • crystal form CSI provided by the present invention in the preparation of a P2X3 receptor blocker medicine.
  • the crystalline form CSI provided by the present invention has no solvent residue. Residual solvents not only affect the safety of the drug, but also have an impact on the quality and stability of the drug. Residual solvents may lead to drug transcrystallization or impurity formation during production and storage, resulting in changes in drug bioavailability and toxic side effects.
  • the crystal form CSI provided by the invention has no solvent residue, and effectively overcomes the disadvantages of low drug stability, poor curative effect and high toxicity caused by low drug purity or high solvent residue.
  • the crystalline form CSI provided by the present invention has higher solubility.
  • the solubility of the crystal form CSI is 1.5 times that of the crystal form A of the prior art WO2018118668A1.
  • Higher solubility is beneficial to improve the absorption of drugs in the human body and improve bioavailability; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the side effects of drugs and improving the safety of drugs.
  • the crystal form CSI API provided by the present invention has better physical and chemical stability and humidity stability. After the crystalline form of CSI APIs are separately packaged and placed under the conditions of 25°C/60%RH, the crystal form has not changed for at least 6 months, and the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form CSI API After the crystalline form CSI API has been sealed and packaged, the crystal form has not changed under the condition of 40°C/75%RH for at least 6 months, and the crystal form has not changed under the condition of 60°C/75%RH for at least 1 month, and The purity remains essentially unchanged during storage. It shows that the crystalline form CSI API has better stability under accelerated conditions and more severe conditions. Meanwhile, the crystalline form CSI has good humidity stability. After the crystal form CSI of the present invention is cycled once under a relative humidity of 40%-95%-0%-95%, the crystal form does not change. Furthermore, the crystalline form CSI did not deliquescence after being placed at room temperature/97%RH for 14 days, indicating that the crystalline form CSI has better stability under high humidity conditions.
  • CSI API High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes and toxic side effects caused by changes in crystal form or impurities.
  • the crystal form CSI API provided by the present invention has good mechanical stability. After grinding, the crystalline form CSI API did not transform into crystals and the crystallinity did not decrease, and had good physical stability. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • Figure 1 shows the XRPD pattern of crystalline form CSI
  • Figure 2 is the DSC diagram of the crystal form CSI
  • Figure 3 is the TGA diagram of the crystal form CSI
  • Figure 4 is the 1 H NMR chart of the crystalline form CSI
  • Figure 5 is the XRPD comparison chart of crystalline CSI before and after being placed under different conditions (from top to bottom: before placing, placed at 25°C/60%RH for 6 months (airtight packaging), placed at 25°C/60%RH for 6 months month (open packaging), 6 months at 40°C/75%RH (airtight packaging), 1 month at 60°C/75%RH (airtight packaging))
  • Figure 6 is the XRPD comparison chart of crystal form CSI before and after DVS test (top: before DVS, bottom: after DVS)
  • Figure 7 is the XRPD comparison chart of the crystal form CSI before and after grinding (top: before grinding, bottom: after grinding)
  • the X-ray powder diffraction pattern of Example 6 of the present invention was collected on a Bruker D8 DISCOVER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • X-ray powder diffraction patterns of other examples described herein were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • test parameters for the detection of crystalline CSI related substances of the present invention are shown in Table 2:
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring speed is preferably 300-900 rev/min, and the mechanical stirring The speed is preferably 100-300 revolutions per minute.
  • the "volatilization” is accomplished by conventional methods in the art, such as slow volatilization or rapid volatilization.
  • the slow volatilization can be by sealing the container with a sealing film, puncturing the holes, and standing to volatilize; the fast volatilization can be by leaving the container open to volatilize.
  • the "cooling" is accomplished by conventional methods in the art, such as slow cooling and rapid cooling.
  • the slow cooling is usually carried out at 0.1°C/min.
  • Rapid cooling usually involves transferring the sample directly from an environment not lower than room temperature, such as a refrigerator, for cooling.
  • the “humidity induction” is accomplished by conventional methods in the art, such as induction by placing the solid under a certain humidity condition.
  • gas-liquid diffusion is accomplished by conventional methods in the art, such as inducing a solution containing a compound in a solvent atmosphere.
  • gas-solid diffusion is accomplished by conventional methods in the art, for example, placing the solid in a solvent atmosphere to induce it.
  • anti-solvent addition is accomplished by conventional methods in the art, such as adding another solvent to the solution containing the compound.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • the "open packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, covering the bottle opening with a layer of aluminum foil and making 5-10 small holes in the aluminum foil.
  • the "airtight packaging" is accomplished by conventional methods in the art, such as placing the sample in a glass vial, closing the bottle cap and sealing it in an aluminum foil bag.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSI of the present invention is pure, substantially free from admixture with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salts as starting materials are in solid form.
  • Compound I and/or its salts used in the following examples may be solids/crystal forms disclosed in the prior art, such as those disclosed in WO2018118668A1.
  • Embodiment 2-3 the preparation method of crystal form CSI
  • the crystalline solids obtained in Examples 2-3 are all of the crystal form CSI of the present invention.
  • the X-ray powder diffraction pattern of the crystal form CSI obtained in Example 2 is shown in FIG. 1
  • the X-ray powder diffraction data is shown in Table 6.
  • the DSC chart of the crystal form CSI obtained in Example 2 is shown in FIG. 2 .
  • the TGA diagram of the crystal form CSI obtained in Example 2 is shown in FIG. 3 , when it is heated to 100° C., it has a mass loss of about 3.5%, which corresponds to the removal of water.
  • one hydrogen with a chemical shift ⁇ of 3.34 was covered by the water peak, and four active hydrogens did not appear.
  • the NMR results showed that the crystalline form CSI was the monocitrate of compound I, and did not contain solvent residues.
  • Placement conditions packing condition put time Crystal form purity start —— —— Form CSI 99.45%
  • the crystalline form CSI can be stable for at least 6 months at 25°C/60%RH; after airtight packaging, the crystalline form CSI can be stable at 40°C/75%RH for at least 6 months. months, it can be seen that the crystalline form CSI can maintain good stability under both long-term and accelerated conditions. After airtight packaging, the crystalline form of CSI is stable for at least 1 month at 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • the crystalline form CSI was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The test results are shown in Figure 7. The results showed that after grinding, the crystal form and crystallinity of crystalline form CSI did not change, and had good stability.

Landscapes

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

Abstract

提供Gefapixant(称为"化合物I")柠檬酸盐的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备P2X3受体拮抗剂药物和治疗慢性咳嗽药物中的用途。提供的化合物I柠檬酸盐的新晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对含化合物I柠檬酸盐药物的优化和开发具有重要价值。

Description

Gefapixant柠檬酸盐的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及Gefapixant柠檬酸盐的晶型及其制备方法和用途。
背景技术
慢性咳嗽为持续超过八周的咳嗽，可由肺部疾病(例如哮喘、慢性阻塞性肺疾病或特发性肺间质纤维化)、肺外疾病(过敏性鼻炎、胃食管反流)、某些药物的副作用，或无法识别的原因引起。慢性咳嗽的咳嗽频率高(每小时10-100次)，并且持续时间长(数月或数年)。
P2X3受体是一种由感觉神经元表达的三磷酸腺苷(ATP)门控离子通道，是治疗慢性致敏病症的靶标。P2X3受体在某些感觉神经的敏化中起关键作用。在气道和肺部的损伤或感染的触发下，这些感觉神经会在由常见细胞信号(ATP)介导的病理状态下被激活或敏化，导致过度、持续和频繁的咳嗽冲动，即慢性咳嗽。Gefapixant是首个非麻醉的P2X3受体阻断剂，可选择性阻断ATP对P2X3受体的激活，并可潜在地用于治疗呼吸道病症和障碍以及其他病症中的咳嗽、慢性咳嗽和咳嗽的冲动。Gefapixant的化学名称为5-(2,4-二氨基-嘧啶-5-基氧基)-4-异丙基-2-甲氧基-苯磺酰胺(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2021123311-appb-000001
晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。
WO2019209607A1公开了化合物I柠檬酸盐甲醇溶剂合物晶型1，异丙醇溶剂合物晶型1和水合甲醇溶剂合物晶型1。WO2019209607A1还公开了化合物I柠檬酸盐可与乙醇/水、异丙醇/水、四氢呋喃或N-甲基吡咯烷酮形成溶剂合物。根据ICH发布的“Q3C杂质：残留溶剂的指导原则”，甲醇，四氢呋喃和N-甲基吡咯烷酮属于2类溶剂，2类溶剂是有动物致 癌性的溶剂，在药品中需严格限制，以保护患者免受潜在不良反应的影响。乙醇在人体内，会被肝脏代谢为乙醛。在国际癌症研究机构的分级中，乙醛属于1级致癌物。异丙醇是一种强效的中枢神经***抑制剂，摄入或吸入中毒可能导致昏迷和呼吸停止。它的代谢产物为丙酮，可能导致并延长中枢神经***的抑制。综上，WO2019209607A1公开的化合物I柠檬酸盐溶剂合物均不适合用于药物开发，且一定程度上说明化合物I柠檬酸盐易得到溶剂合物。
WO2018118668A1公开了化合物I柠檬酸盐晶型A和晶型B，其说明书还披露了“推测晶型A可能是热力学上最稳定的柠檬酸盐无水形式”。但核磁数据显示晶型A和晶型B均有溶剂残留。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。此外，残留溶剂本身也会影响药物的安全性。为克服现有技术的缺点，仍然需要一种符合药用标准的新晶型，以用于含化合物I药物的开发。
化合物I柠檬酸盐极易形成溶剂合物，想要获得一种符合药用标准的新晶型非常困难。本申请发明人研究发现，除了WO2019209607A1专利中公开的溶剂合物以外，化合物I柠檬酸盐还能和其它多种溶剂(2-甲基四氢呋喃、三氟乙醇、二溴甲烷、对二甲苯、苯甲醚、正丁醇、甲苯等)形成溶剂合物或水合溶剂合物。本申请发明人尝试多种实验方法(例如挥发、降温、湿度诱导、反溶剂添加、气液扩散和气固扩散等)，开展了一千多个实验，均未得到符合药用标准的新晶型。其中，挥发的实验方法极容易得到化合物I柠檬酸盐无定形，即使本申请发明人进行了大量的实验研究，包括尝试多种单一或者混合溶剂，改变挥发的起始浓度、溶剂的混合比例以及改变挥发溶液的体积和改变挥发的温度等，也难以得符合药用标准的新晶型。在付出大量的创造性劳动后，终于创造性的发现了本发明所述晶型CSI。其在溶残、溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是没有溶残、溶解度高，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。
发明内容
本发明提供化合物I柠檬酸盐新晶型，包含该新晶型的制备方法和用途及其药物组合物。
根据本发明的目的，本发明提供化合物I柠檬酸盐晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为6.6°±0.2°、11.7°±0.2°、20.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为10.5°±0.2°、13.9°±0.2°、18.5°±0.2°中的任意一处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为10.5°±0.2°、13.9°±0.2°、18.5°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为18.0°±0.2°、23.8°±0.2°、24.7°±0.2°中的任意一处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为18.0°±0.2°、23.8°±0.2°、24.7°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为6.6°±0.2°、11.7°±0.2°、20.0°±0.2°、10.5°±0.2°、13.9°±0.2°、18.5°±0.2°、18.0°±0.2°、23.8°±0.2°、24.7°±0.2°、9.9°±0.2°、16.7°±0.2°、22.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处有特征峰。
非限制性地，晶型CSI的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSI的差示扫描量热分析图基本如图2所示。
非限制性地，晶型CSI的热重分析图基本如图3所示，加热至100℃具有约3.5％的质量损失，对应水的脱去。
非限制性地，晶型CSI为水合物晶型。
另一方面，本发明还提供晶型CSI的制备方法，其特征在于，所述制备方法包括：将化合物I柠檬酸盐固体溶解于水和醇类的混合溶剂中，慢速挥发得到晶型CSI。
进一步地，所述醇类优选三氟乙醇；所述慢速挥发的温度优选2-40℃；所述混合溶剂的比例(水：醇类，v:v)为1:25-1:2。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI及药学上可接受的辅料。
进一步地，本发明提供的晶型CSI在制备P2X3受体阻断剂药物中的用途。
更进一步地，本发明提供的晶型CSI在制备治疗慢性咳嗽药物中的用途。
有益效果
本发明提供的晶型CSI具有以下优势：
(1)与现有技术相比，本发明提供的晶型CSI无溶剂残留。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSI无溶剂残留，有效地克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(2)与现有技术相比，本发明提供的晶型CSI具有更高的溶解度。特别是在水中，晶型CSI的溶解度是现有技术WO2018118668A1晶型A的1.5倍。更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度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。
(3)本发明提供的晶型CSI原料药有较好的物理化学稳定性和湿度稳定性。晶型CSI原料药分别经过开口和密闭包装后，在25℃/60％RH条件下放置，至少6个月晶型未发生变化，且储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。
晶型CSI原料药经过密闭包装后，在40℃/75％RH条件下放置至少6个月晶型未发生变化，在60℃/75％RH条件下至少1个月晶型未发生变化，且储存过程中纯度基本保持不 变。说明晶型CSI原料药在加速条件及更严苛的条件下，具有较好的稳定性。同时，晶型CSI具有良好的湿度稳定性。本发明晶型CSI在40％-95％-0％-95％相对湿度下循环一次后，晶型未发生变化。更进一步，晶型CSI置于室温/97％RH条件下14天后，没有潮解，说明晶型CSI在高湿的条件下具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSI具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化和毒副作用。
(4)本发明提供的晶型CSI原料药有良好的机械稳定性。晶型CSI原料药研磨后未转晶且结晶度没有下降，具有良好的物理稳定性。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。
附图说明
图1为晶型CSI的XRPD图
图2为晶型CSI的DSC图
图3为晶型CSI的TGA图
图4为晶型CSI的 1H NMR图
图5为晶型CSI在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH放置6个月(密闭包装)，25℃/60％RH放置6个月(开口包装)，40℃/75％RH放置6个月(密闭包装)，60℃/75％RH放置1个月(密闭包装))
图6为晶型CSI在DVS测试前后的XRPD对比图(上：DVS前，下：DVS后)
图7为晶型CSI研磨前后的XRPD对比图(上：研磨前，下：研磨后)
具体实施方式
结合以下实施例对本发明做详细说明，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
DVS：动态水分吸附
LC：液相色谱
1H NMR：液态核磁氢谱
RH：相对湿度
采集数据所用的仪器及方法：
本发明所述实施例6的X射线粉末衍射图在Bruker D8 DISCOVER 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
Figure PCTCN2021123311-appb-000002
1.54060；
Figure PCTCN2021123311-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：40仟伏特(kV)
电流：40毫安培(mA)
扫描范围(2θ)：自4.0至40.0度
本发明所述的其他实施例的X射线粉末衍射图在Bruker D2 PHASER 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
Figure PCTCN2021123311-appb-000004
1.54060；
Figure PCTCN2021123311-appb-000005
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围(2θ)：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
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱 仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明所述晶型CSI动态溶解度测试参数如表1所示：
表1
Figure PCTCN2021123311-appb-000006
本发明所述晶型CSI有关物质检测的测试参数如表2所示：
表2
Figure PCTCN2021123311-appb-000007
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌速度优选300-900转/分钟，机械搅拌速度优选 100-300转/分钟。
所述“挥发”，采用本领域的常规方法完成，例如慢速挥发或快速挥发。慢速挥发可以是将容器封上封口膜，扎孔，静置挥发；快速挥发可以是将容器敞口放置挥发。
所述“降温”，采用本领域的常规方法完成，例如缓慢降温和快速降温。缓慢降温通常以0.1℃/分钟进行。快速降温通常是将样品从不低于室温的环境直接转移如冰箱中进行降温操作。
所述“湿度诱导”，采用本领域的常规方法完成，例如将固体置于一定湿度条件下诱导。
所述“气液扩散”，采用本领域的常规方法完成，例如将含有化合物的溶液置于溶剂气氛中诱导。
所述“气固扩散”，采用本领域的常规方法完成，例如将固体置于溶剂气氛中诱导。
所述“反溶剂添加”，采用本领域的常规方法完成，例如向含有化合物的溶液中加入另一种溶剂。
所述“干燥”，采用本领域的常规方法完成，例如真空干燥，鼓风干燥或自然晾干。干燥温度可以是室温或更高，优选室温到约60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“开口包装”，采用本领域的常规方法完成，例如将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开5-10个小孔。
所述“密闭包装”，采用本领域的常规方法完成，例如将样品置于玻璃小瓶中，盖上瓶盖后密封于铝箔袋中。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射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X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图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CSI是纯的，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。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是特定的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述化合物I和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I和/或其盐为固体形式。
以下实施例中所使用的化合物I和/或其盐可以是现有技术公开的固体/晶型，例如WO2018118668A1公开的固体。
实施例1
称量如表3所示适量的化合物I固体和柠檬酸固体于玻璃瓶中，加入一定体积的溶剂后，在一定温度下搅拌，得到固体。或者称量如表3所示适量的化合物I固体于玻璃瓶中，加入一定体积的1M柠檬酸水溶液，和一定体积的溶剂后，在一定温度下搅拌，得到固体。结果表明，化合物I柠檬酸盐极易形成溶剂合物。
表3
Figure PCTCN2021123311-appb-000008
称取如表4所示一定量的化合物I柠檬酸盐固体，向其中加入表4所示一定体积的溶剂，得到澄清溶液，取一定体积过滤后的溶液在不同温度下挥发得到干燥的结晶固体。结果表明，挥发实验容易得到化合物I柠檬酸盐无定形。
表4
Figure PCTCN2021123311-appb-000009
Figure PCTCN2021123311-appb-000010
实施例2-3：晶型CSI的制备方法
称取一定量的化合物I柠檬酸盐固体，向其中加入表5中一定体积的溶剂，得到澄清溶液，取1mL溶液过滤后慢速挥发得到干燥的结晶固体。
表5
Figure PCTCN2021123311-appb-000011
经检测，实施例2-3所得结晶固体均为本发明晶型CSI。实施例2所得晶型CSI的X射线粉末衍射图如图1所示，X射线粉末衍射数据如表6所示。实施例2所得晶型CSI的DSC图如图2所示。实施例2所得晶型CSI的TGA图如图3所示，将其加热至100℃时，具有约3.5％的质量损失，对应水的脱去。实施例2所得晶型CSI的核磁数据为： 1H NMR(400MHz,DMSO-d6)δ7.33(s,1H),7.09(s,1H),7.05(s,1H),7.03(s,2H),6.98(s,2H),6.32(s,2H),3.90(s,3H),2.69(d,J＝15.3Hz,2H),2.60(d,J＝15.3Hz,2H),1.26(d,J＝6.9Hz,6H)。其中， 化学位移δ为3.34的一个氢被水峰掩盖，四个活泼氢未出峰。核磁结果表明：晶型CSI为化合物I的一柠檬酸盐，且不含有溶剂残留。
实施例3所得晶型CSI的X射线粉末衍射数据如表7所示。
表6
衍射角2θ d值 强度％
6.59 13.42 21.52
9.95 8.89 5.66
10.54 8.39 11.80
11.69 7.57 100.00
12.44 7.12 2.27
13.87 6.38 20.63
14.99 5.91 7.13
16.31 5.43 2.33
16.70 5.31 8.67
17.97 4.94 13.67
18.54 4.79 30.80
18.99 4.67 7.08
20.04 4.43 94.54
20.50 4.33 11.49
21.27 4.18 24.41
21.85 4.07 3.22
22.58 3.94 9.51
23.55 3.78 19.78
23.79 3.74 39.45
24.29 3.66 6.53
24.71 3.60 18.06
26.00 3.43 7.79
26.22 3.40 9.70
27.14 3.29 10.62
27.68 3.22 7.53
29.74 3.00 5.06
31.21 2.87 5.29
32.19 2.78 3.02
32.64 2.74 2.56
33.83 2.65 1.17
34.76 2.58 3.00
35.71 2.51 2.17
36.78 2.44 2.74
37.60 2.39 1.69
表7
衍射角2θ d值 强度％
6.57 13.45 24.39
9.91 8.92 3.12
10.52 8.41 7.06
11.69 7.57 84.35
13.87 6.38 17.62
14.98 5.91 5.18
15.18 5.84 3.85
16.71 5.31 5.66
17.96 4.94 9.73
18.54 4.79 18.79
18.97 4.68 6.81
20.03 4.43 100.00
20.50 4.33 16.32
21.26 4.18 29.56
22.60 3.93 6.36
23.55 3.78 24.08
23.78 3.74 27.21
24.26 3.67 8.40
24.71 3.60 14.93
26.23 3.40 10.93
26.61 3.35 4.97
26.97 3.31 10.69
27.67 3.22 9.20
29.97 2.98 4.96
31.22 2.87 5.77
31.58 2.83 3.13
32.16 2.78 3.19
32.65 2.74 2.75
34.31 2.61 1.83
34.74 2.58 3.20
35.14 2.55 2.02
35.64 2.52 3.18
36.81 2.44 3.75
实施例4：晶型CSI的制备方法
称取21.9mg的化合物I柠檬酸盐固体，向其中加入2mL的水/三氟乙醇(1:10,v/v)，得到澄清溶液。把该溶液过滤到含有10mL的三氟乙醇的玻璃瓶中(含有约1mg的晶型CSI晶种)。进一步的，把该溶液置于5℃冰箱中三周后，敞口置于5℃下快速挥发6周，得到本发明所述晶型CSI。把该固体置于30℃真空烘箱中干燥两天后，晶型不变。干燥后的晶型CSI的 1H NMR如图4所示，核磁数据为： 1H NMR(400MHz,DMSO-d6)δ7.32(s,1H),7.10(s,1H),7.06(s,3H),7.04(s,2H),6.43(s,2H),3.90(s,3H),3.34(hept,J＝6.9Hz,1H),2.68(d,J＝15.3Hz,2H),2.59(d,J＝15.3Hz,2H),1.26(d,J＝6.9Hz,6H)，其中，柠檬酸的三个羧基上的活泼氢和羟基上的一个活泼氢未出现。
实施例5：晶型CSI的动态溶解度
取本发明的晶型CSI及现有技术晶型A各约25mg分别分散在2mL的水中，配制成饱和溶液，平衡1小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表8所示。
表8
Figure PCTCN2021123311-appb-000012
结果表明，晶型CSI在水中具有更高的溶解度，晶型CSI的溶解度是现有技术晶型A的1.5倍。
实施例6：晶型CSI的稳定性
称取适量本发明晶型CSI，开口或密闭包装后，分别放置在25℃/60％RH、40℃/75％RH和60℃/75％RH条件下，采用LC和XRPD测定纯度与晶型。结果如表9所示，XRPD对比图如图5所示。
表9
放置条件 包装条件 放置时间 晶型 纯度
起始 —— —— 晶型CSI 99.45％
25℃/60％RH 密闭 6个月 晶型CSI 99.41％
25℃/60％RH 开口 6个月 晶型CSI 99.46％
40℃/75％RH 密闭 6个月 晶型CSI 99.47％
60℃/75％RH 密闭 1个月 晶型CSI 99.48％
结果表明，经过分别开口和密闭包装后，晶型CSI在25℃/60％RH条件下可至少稳定6个月；密闭包装后，晶型CSI在40℃/75％RH条件下至少可稳定6个月，可见，晶型CSI在长期和加速条件下均可保持良好的稳定性。密闭包装后，晶型CSI在60℃/75％RH条件下至少可稳定1月，可见在更严苛的条件下稳定性也很好。
实施例7：晶型CSI的湿度稳定性
取适量本发明晶型CSI，采用动态水分吸附仪(DVS)测试其湿度稳定性。25℃下，在40％-95％-0-95％相对湿度下循环一次，并在DVS测试前后，用XRPD测试晶型。DVS前后的XRPD对比图如图6所示。结果表明，DVS测试前后，晶型CSI未发生变化。
取适量的晶型CSI置于玻璃瓶中，之后把该样品置于室温/97％RH条件下14天，取出样品，观察固体状态。结果表明，晶型CSI放置于室温/97％RH条件下14天后没有潮解。
实施例8：晶型CSI的机械稳定性
将晶型CSI置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如图7所示。结果表明，在研磨后，晶型CSI的晶型和结晶度无变化，具有较好的稳定性。
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 (9)

  1. 化合物I
    Figure PCTCN2021123311-appb-100001
    柠檬酸盐晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.6°±0.2°、11.7°±0.2°、20.0°±0.2°处具有特征峰。
  2. 根据权利要求1所述的柠檬酸盐晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为10.5°±0.2°、13.9°±0.2°、18.5°±0.2°中的任意一处具有特征峰。
  3. 根据权利要求1所述的柠檬酸盐晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.0°±0.2°、23.8°±0.2°、24.7°±0.2°中的任意一处具有特征峰。
  4. 根据权利要求2所述的柠檬酸盐晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.0°±0.2°、23.8°±0.2°、24.7°±0.2°中的任意一处具有特征峰。
  5. 一种权利要求1所述的柠檬酸盐晶型CSI的制备方法，其特征在于：将化合物I柠檬酸盐固体溶解于水和醇类的混合溶剂中，慢速挥发得到柠檬酸盐晶型CSI。
  6. 根据权利要求5所述的制备方法，所述醇类是三氟乙醇。
  7. 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中所述的柠檬酸盐晶型CSI及药学上可接受的辅料。
  8. 权利要求1中所述的柠檬酸盐晶型CSI在制备P2X3受体阻断剂药物中的用途。
  9. 权利要求1中所述的柠檬酸盐晶型CSI在制备治疗慢性咳嗽药物中的用途。
PCT/CN2021/123311 2020-10-19 2021-10-12 Gefapixant柠檬酸盐的晶型及其制备方法和用途 WO2022083476A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011119447.2 2020-10-19
CN202011119447 2020-10-19

Publications (1)

Publication Number Publication Date
WO2022083476A1 true WO2022083476A1 (zh) 2022-04-28

Family

ID=81291609

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/123311 WO2022083476A1 (zh) 2020-10-19 2021-10-12 Gefapixant柠檬酸盐的晶型及其制备方法和用途

Country Status (1)

Country Link
WO (1) WO2022083476A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087654A (zh) * 2016-12-20 2019-08-02 传入制药公司 P2x3拮抗剂的结晶盐和多晶型物
WO2019209607A1 (en) * 2018-04-23 2019-10-31 Merck Sharp & Dohme Corp. Novel process for synthesis of a phenoxy diaminopyrimidine compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110087654A (zh) * 2016-12-20 2019-08-02 传入制药公司 P2x3拮抗剂的结晶盐和多晶型物
WO2019209607A1 (en) * 2018-04-23 2019-10-31 Merck Sharp & Dohme Corp. Novel process for synthesis of a phenoxy diaminopyrimidine compound

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MALONEY, K.M. ET AL.: "Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 24, 23 October 2020 (2020-10-23), XP055862885 *
MOHAN ANNE E., DIBENEDETTO MICHAEL, ALWEDI EMBAREK, ANG YEE SWAN, ASI SIHOMBING MUHAMMAD SOFIAN BIN, CHANG HSIEH YAO D., COTE AARO: "Development and Demonstration of a Co-feed Process to Address Form and Physical Attribute Control of the Gefapixant (MK-7264) Citrate Active Pharmaceutical Ingredient", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 25, no. 3, 19 March 2021 (2021-03-19), US , pages 541 - 551, XP055922952, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.0c00488 *
REN, H. ET AL.: "Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 24, 16 October 2020 (2020-10-16), XP055859791 *

Similar Documents

Publication Publication Date Title
WO2022170864A1 (zh) Belumosudil甲磺酸盐的晶型及其制备方法和用途
CN108864077B (zh) 小檗碱有机酸盐的固体形式及其制备方法
WO2022121670A1 (zh) Tolebrutinib的晶型及其制备方法和用途
CN114728899B (zh) 新型三苯基化合物盐
WO2021244323A1 (zh) 一种乌帕替尼的晶型及其制备方法和用途
WO2021129589A1 (zh) Kd-025的新晶型及其制备方法
WO2014082354A1 (zh) 西达本胺的晶型及其制备方法与应用
KR102572035B1 (ko) 무정형 형태의 빌란테롤 트리페나테이트 및 이의 제조방법
CN117295735A (zh) Tolebrutinib晶型、无定型及其制备方法和用途
WO2022122014A1 (zh) Lanifibranor的晶型及其制备方法和用途
WO2021129465A1 (zh) 一种Resmetirom晶型及其制备方法和用途
WO2021143498A1 (zh) 一种Deucravacitinib的晶型及其制备方法和用途
KR20230038229A (ko) 우파다시티닙의 결정형, 이의 제조 방법 및 이의 용도
WO2022083476A1 (zh) Gefapixant柠檬酸盐的晶型及其制备方法和用途
EP4048404A1 (en) Polymorphs of avapritinib and methods for preparing the polymorphs
WO2019205812A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2022052822A1 (zh) Resmetirom的晶型及其制备方法和用途
WO2022036782A1 (zh) 一种雄激素受体拮抗剂药物的晶型csvi及其制备方法和用途
WO2021000687A1 (zh) Pac-1晶型的制备方法
US10815232B2 (en) Crystalline forms of viral-protein inhibitor drug VX-787, processes for preparation thereof and use thereof
WO2018001335A1 (zh) Nbi-98854的晶型及其制备方法和用途
WO2022048675A1 (zh) Risdiplam晶型及其制备方法和用途
WO2023143321A1 (zh) 他伐帕敦的晶型及其制备方法和用途
EP3412661A1 (en) Cocrystals of vortioxetine hydrobromide and resorcinol
WO2024104268A1 (zh) 艾拉司群二盐酸盐的共晶及其制备方法和用途

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: 21881894

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: 21881894

Country of ref document: EP

Kind code of ref document: A1