WO2020048299A1 - Pharmaceutical cocrystal and preparation method therefor - Google Patents

Pharmaceutical cocrystal and preparation method therefor Download PDF

Info

Publication number
WO2020048299A1
WO2020048299A1 PCT/CN2019/100468 CN2019100468W WO2020048299A1 WO 2020048299 A1 WO2020048299 A1 WO 2020048299A1 CN 2019100468 W CN2019100468 W CN 2019100468W WO 2020048299 A1 WO2020048299 A1 WO 2020048299A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
ralinepag
ray powder
powder diffraction
diffraction pattern
Prior art date
Application number
PCT/CN2019/100468
Other languages
French (fr)
Chinese (zh)
Inventor
张�杰
陈勇
罗忠华
黄芳芳
Original Assignee
广东东阳光药业有限公司
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 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to CN201980057194.XA priority Critical patent/CN112638865B/en
Publication of WO2020048299A1 publication Critical patent/WO2020048299A1/en

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

Definitions

  • the invention belongs to the technical field of medicine and chemical engineering, and particularly relates to a drug co-crystal and a preparation method thereof.
  • Ralinepag is a novel oral selective IP receptor agonist for the treatment of pulmonary hypertension (PAH) by the prostacyclin pathway.
  • PAH pulmonary hypertension
  • Ralinepag is effective in vasodilation, inhibition of vascular smooth muscle cell proliferation, and inhibition of platelet aggregation, and has a longer half-life. These characteristics make it a potentially best-in-class drug for treating PAH.
  • Ralinepag structure is shown in the following formula (X):
  • Ralinepag has the disadvantages of slow dissolution rate, low in vitro dissolution rate, and low bioavailability, which has a certain effect on drug absorption. So it is urgent to find a way to improve the dissolution of Ralinepag. To solve this problem, the inventors carried out related research on Ralinepag crystal form.
  • the present invention mainly relates to a co-crystal formed by a compound (Ralinepag) represented by formula (X) and isonicotinoid.
  • a specific compound co-crystal of formula (X) is advantageous because this co-crystal form can make the dissolution rate of the compound represented by formula (X) to a certain extent, It is a good solution to the disadvantages that the compound represented by formula (X) has a slow dissolution rate, a low dissolution rate in vitro, and a low bioavailability.
  • a first aspect of the present invention provides a co-crystal formed by a compound represented by formula (X) and isonicotinoid.
  • the second aspect of the present invention provides a method for preparing the co-crystal.
  • substantially as shown refers to a certain "crystalline form” that is substantially pure and whose X-ray powder diffraction pattern is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks appear in the given X-ray powder diffraction pattern.
  • X-ray powder diffraction pattern is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks appear in the given X-ray powder diffraction pattern.
  • relative intensity refers to a ratio of the intensity of the other peak to the intensity of the first strong peak when the intensity of the first strong peak in a group of diffraction peaks belonging to a certain crystal form is defined as 100%.
  • the values of 2 ⁇ (also known as 2theta or diffraction peak) in the X-ray powder diffraction pattern are all in degrees (°).
  • the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
  • the X-ray powder diffraction peak of the crystal the measurement of the 2 ⁇ or diffraction peak of its X-ray powder diffraction pattern has experimental errors, between one machine and another machine, and between one sample and another sample,
  • the measurement of the 2 ⁇ or diffraction peak of the X-ray powder diffraction pattern may be slightly different, and the value of the experimental error or difference may be +/- 0.2 units or +/- 0.1 units or +/- 0.05 units, Therefore, the value of the 2 ⁇ or diffraction peak cannot be regarded as absolute.
  • the differential scanning calorimetry curve (DSC) of the crystal has experimental errors.
  • the position and peak of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample.
  • the value of the experimental error or difference may be 5 ° C or lower, or 4 ° C or lower, or 3 ° C or lower, or 2 ° C or lower, or 1 ° C or lower. Therefore, the peak position or Values cannot be considered absolute.
  • thermogravimetric analysis curve (TGA) of the crystal.
  • the endothermic curve or weight loss rate may be slightly different between one machine and another, and between one sample and another.
  • the experimental error Or the difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as absolute.
  • Root temperature means a temperature between about 20 ° C and 35 ° C or about 23 ° C and 28 ° C or about 25 ° C.
  • good solvent may be a single solvent or a mixed solvent, and means that the compound represented by formula (X) has a solubility in the single solvent or mixed solvent of greater than 1 g / L, or greater than 2 g / L, or greater than 3 g / L, or Greater than 4g / L, or greater than 5g / L, or greater than 6g / L, or greater than 7g / L, or greater than 8g / L, or greater than 9g / L, or greater than 10g / L, or greater than 15g / L, or greater than 20g / L, or greater than 30g / L, or greater than 40g / L, or greater than 50g / L, or greater than 60g / L, or greater than 70g / L, or greater than 80g / L, or greater than 100g / L.
  • the solubility of the compound represented by formula (X) in a good solvent is greater than that of the poor solvent; in some embodiments, the difference between the solubility of the good solvent and the poor solvent for the compound represented by the formula (X) is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, the solubility of a good solvent for a compound represented by formula (X) is less than that of a poor solvent Large, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
  • the inventors have developed a co-crystal formed by a compound represented by formula (X) and isonicotine through research.
  • a co-crystal formed by a compound represented by the formula (X) and isonicotinoid has the following characteristics: the compound represented by the formula (X) and isoniatin exist in a 1: 1 molar ratio.
  • the co-crystal formed by the compound represented by formula (X) and isonicotinoid has the following characteristics: the X-ray powder diffraction pattern thereof at 2 ⁇ is approximately 6.8, 10.1, 15.1, 16.9, 19.5, 21.1, 22.6, 24.5, and / Or there is a peak at 27.3 degrees.
  • the co-crystals formed by the compound represented by formula (X) and isonicotinoid have the following characteristics: the X-ray powder diffraction pattern thereof at 2 ⁇ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1 There are peaks at, 22.6, 24.5, and / or 27.3 degrees.
  • the X-ray powder diffraction pattern of the eutectic at 2 ⁇ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 22.6, 22.9, 24.1, 24.5, 27.3, and 30.6 degrees. There are peaks at one or more locations.
  • the X-ray powder diffraction pattern of the co-crystal at 2 ⁇ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 21.9, 22.6, 22.9, 23.7, 24.1, 24.5, 26.5 There are peaks at one or more of the positions of 27.3, 30.2, and 30.6 degrees.
  • the X-ray powder diffraction pattern of the co-crystal is shown in FIG. 1, wherein the relative intensity of the peak at 2 ⁇ of about 22.60 degrees is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%. %, Or greater than 99%.
  • the eutectic also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at about 100 ° C to 150 ° C. In a specific embodiment, the eutectic differential scanning calorimetry curve (DSC) has an endothermic peak at about 125 ° C-150 ° C. In a specific embodiment, the eutectic differential scanning quantity The thermal curve (DSC) has an endothermic peak at about 130 ° C-140 ° C, and the peak end value of the endothermic peak is about 138 ° C. In some embodiments, the differential scanning calorimetry (DSC) of the eutectic is shown in FIG. 2.
  • the eutectic thermogravimetric analysis curve (TGA) has a weight loss of less than 2% at about 30 ° C to 150 ° C. In a specific embodiment, the eutectic thermogravimetric analysis curve (TGA) has a weight loss of less than 1.05% at about 30 ° C to 150 ° C; in a specific embodiment, the eutectic thermogravimetric analysis curve (TGA) is shown in Figure 3.
  • the co-crystal formed by the compound represented by formula (X) and isonicotinoid is a powder with good appearance and fluidity, and has good properties in terms of dissolution, fluidity, etc., which is beneficial to storage, transfer and production processes. It is suitable for preparation into a pharmaceutical composition.
  • the co-crystals formed by the compound represented by the formula (X) and isonicotinoid are stable and have good solubility, and can be used for preparing pharmaceutical preparations for treating diseases such as pulmonary hypertension (PAH), or for inhibiting the proliferation of vascular smooth muscle cells or Pharmaceutical preparations that inhibit platelet aggregation.
  • diseases such as pulmonary hypertension (PAH)
  • PAH pulmonary hypertension
  • Pharmaceutical preparations that inhibit platelet aggregation are stable and have good solubility, and can be used for preparing pharmaceutical preparations for treating diseases such as pulmonary hypertension (PAH), or for inhibiting the proliferation of vascular smooth muscle cells or Pharmaceutical preparations that inhibit platelet aggregation.
  • PAH pulmonary hypertension
  • the present invention provides a method for preparing the co-crystal.
  • a method for preparing a co-crystal formed by a compound represented by the formula (X) and isoniatin comprising: dissolving the compound represented by the formula (X) and isoniatin in a good solvent, volatilizing the solvent at room temperature to obtain The co-crystals described above.
  • the good solvent is a lower aliphatic alcohol.
  • the lower aliphatic alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and t-butanol. Or more.
  • the good solvent is methanol or ethanol or a combination thereof.
  • the method for preparing the co-crystals includes: completely dissolving the compound represented by formula (X) and isonicotinoid in a good solvent, basically drying the solvent at room temperature, and then vacuum drying to constant weight, The co-crystal is obtained. In some embodiments, the method for preparing the co-crystals includes: completely dissolving the compound represented by formula (X) and isonicotinoid in a good solvent, basically drying the solvent at room temperature, and vacuum drying at 50 ° C for 24 hours. The co-crystal is obtained.
  • FIG. 1 shows an X-ray powder diffraction pattern of a co-crystal formed by the compound represented by the formula (X) obtained in Example 1 and isoniatin.
  • FIG. 2 shows a differential scanning thermal curve (DSC) of a co-crystal formed from the compound represented by the formula (X) obtained in Example 1 and isoniatin.
  • FIG. 3 shows a thermogravimetric analysis chart (TGA) of a co-crystal formed from the compound represented by the formula (X) obtained in Example 1 and isonicotinoid.
  • FIG. 4 shows an X-ray powder diffraction pattern of a co-crystal formed by the compound (X) and isonicotinoid in Example 5.
  • FIG. 5 shows a differential scanning thermal curve (DSC) of a co-crystal formed by the compound (X) and isonicotinoid in Example 5.
  • DSC differential scanning thermal curve
  • FIG. 6 shows an X-ray powder diffraction pattern of the free acid of the compound of (X) in Example 5.
  • FIG. 7 shows a differential scanning thermal curve (DSC) of a compound's free acid in (X) in Example 5.
  • the reagents used in the present invention are all commercially available or can be prepared by the method described in the present invention.
  • mg means milligram
  • mL means milliliter
  • rpm means revolutions per minute
  • h means hour.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3 * 15 zero background sample holder for a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2 / K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40mA.
  • the beam divergence of X-rays which is the effective size of the X-ray constraint on the sample, is 6.6mm. ⁇ continuous scan mode, the effective 2 ⁇ range of 3 ° ⁇ 60 ° is obtained.
  • DSC Differential scanning calorimetry
  • DSC measurements were performed in a TA Instruments Model Q2000 using a sealed disc device.
  • the sample (about 1 to 3 mg) was weighed in an aluminum pan, capped with Tzero, accurately recorded to one hundredth of a milligram, and the sample was transferred to the instrument for measurement.
  • the instrument was purged with nitrogen at 50 mL / min. Data were collected between 30 ° C and 300 ° C at a heating rate of 10 ° C / min. The endothermic peak was plotted downward, and the data was analyzed and displayed by TA Universal Analysis.
  • TGA data on TA Instruments Q500 Use a certified nickel to calibrate the temperature of the instrument.
  • a 8-12 mg sample is usually loaded on a pre-weighed platinum crucible and heated from 30 ° C to 300 ° C at 10 ° C / min. Maintain a nitrogen sweep of 60 mL / min over the sample.
  • the abscissa represents temperature (Temperature, ° C)
  • the ordinate represents the percentage content of weight loss (Weight (%)).
  • a 10mL PE tube was charged with 129.6mg of Ralinepag, 36.6mg of isonicotinoid and 6.0mL of methanol solvent, magnetically stirred at 250rpm, and the solid was completely dissolved at room temperature (about 28.0 ° C) to form a solution.
  • the solution was naturally volatilized at room temperature for about 3 days.
  • the solvent was basically evaporated to dryness. Vacuum drying at 50 ° C for 24 h gave about 165.5 mg of a white solid. It was determined to be Ralinepag / isonicotine co-crystal.
  • the TGA spectrum is basically consistent with Figures 2 and 3, respectively.
  • Ralinepag / isonicotine co-crystals and Ralinepag free acid crystalline forms were subjected to influencing factor experiments, including high temperature tests, The high humidity test and strong light irradiation test are used to investigate the conditions that affect the stability of its crystal form, as shown in Table 1 below.
  • High humidity test Take appropriate amounts of Ralinepag / isonicotine co-crystals and Ralinepag free acid crystal form samples, place them in a weighing bottle, place them in a 25 ° C, RH92.5 ⁇ 5% constant temperature and humidity box, and place them in About 0 mg of the above sample was taken on 0, 5 and 15 days, and its crystal form was tested by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The results are shown in Figure 4-7.
  • XRPD powder X-ray powder diffraction
  • DSC differential scanning calorimetry

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention belongs to the technical field of pharmaceutical and chemical engineering and mainly provides a pharmaceutical cocrystal and a preparation method therefor. The pharmaceutical cocrystal is formed by ralinepag and isonicotine and has advantages of having good stability and high solubility and being suitable for preparing a pharmaceutical composition.

Description

药物共晶体及其制备方法Drug co-crystal and preparation method thereof 技术领域Technical field
本发明属于医药化工技术领域，具体涉及药物共晶体及其制备方法。The invention belongs to the technical field of medicine and chemical engineering, and particularly relates to a drug co-crystal and a preparation method thereof.
背景技术Background technique
Ralinepag(APD811，CAS号：1187856-49-0)是新型口服选择性IP受体激动剂，用于前列环素途径治疗肺动脉高压(PAH)。Ralinepag在血管舒张、抑制血管平滑肌细胞增殖和抑制血小板聚集等方面的药效良好，药物半衰期也更长。这些特点使其成为治疗PAH的潜在同类最佳(best-in-class)药物。Ralinepag结构如下式(X)所示：Ralinepag (APD811, CAS number: 1187856-49-0) is a novel oral selective IP receptor agonist for the treatment of pulmonary hypertension (PAH) by the prostacyclin pathway. Ralinepag is effective in vasodilation, inhibition of vascular smooth muscle cell proliferation, and inhibition of platelet aggregation, and has a longer half-life. These characteristics make it a potentially best-in-class drug for treating PAH. Ralinepag structure is shown in the following formula (X):
Figure PCTCN2019100468-appb-000001
Figure PCTCN2019100468-appb-000001
Ralinepag存在溶解速度慢、体外溶出度低、生物利用度低的缺点，对药物的吸收有一定的影响。所以寻求提高Ralinepag溶出度的方法迫在眉睫。为解决这一问题，发明人对Ralinepag晶型进行了相关研究。Ralinepag has the disadvantages of slow dissolution rate, low in vitro dissolution rate, and low bioavailability, which has a certain effect on drug absorption. So it is urgent to find a way to improve the dissolution of Ralinepag. To solve this problem, the inventors carried out related research on Ralinepag crystal form.
发明内容Summary of the Invention
发明概述Summary of invention
本发明主要涉及式(X)所示的化合物(Ralinepag)和异烟碱形成的共晶体。与他们的游离形式比较，特定的式(X)所示的化合物共晶体是有利的，因为这种共晶的形式能够使得式(X)所示的化合物的溶出速率有一定程度的提高，较好的解决式(X)所示的化合物溶解速度慢、体外溶出度低、生物利用度低的缺点。The present invention mainly relates to a co-crystal formed by a compound (Ralinepag) represented by formula (X) and isonicotinoid. Compared with their free form, a specific compound co-crystal of formula (X) is advantageous because this co-crystal form can make the dissolution rate of the compound represented by formula (X) to a certain extent, It is a good solution to the disadvantages that the compound represented by formula (X) has a slow dissolution rate, a low dissolution rate in vitro, and a low bioavailability.
本发明第一方面提供了式(X)所示的化合物和异烟碱形成的共晶体。A first aspect of the present invention provides a co-crystal formed by a compound represented by formula (X) and isonicotinoid.
本发明第二方面提供了所述的共晶体的制备方法。The second aspect of the present invention provides a method for preparing the co-crystal.
术语定义Definition of Terms
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。The invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the invention as defined by the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents, and similar materials are different or inconsistent with this application (including but not limited to the defined terms, term applications, described technologies, etc.), Prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意合适的子组合提供。It should be further recognized that certain features of the invention have been described in multiple independent embodiments for clarity, but may also be provided in combination in a single embodiment. Conversely, various features of the invention have been described in a single embodiment for simplicity, but may also be provided separately or in any suitable subcombination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和1994年第75版《化学和物理手册》一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions used herein shall apply. For the purposes of this invention, the chemical elements are in accordance with the CAS version of the Periodic Table of Elements, in accordance with the Handbook of Chemistry and Physics, 1994, 75th edition. In addition, the general principles of organic chemistry can be described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire contents of which are incorporated herein by reference.
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" or "including" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other aspects.
术语“基本上如图所示”是指基本上纯净的某种“晶型”其X-射线粉末衍射图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在所给出的X-射线粉末衍射图中。当样品中某种晶型的含量逐渐降低时，其X-射线粉末衍射图中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。The term "substantially as shown" refers to a certain "crystalline form" that is substantially pure and whose X-ray powder diffraction pattern is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks appear in the given X-ray powder diffraction pattern. When the content of a certain crystal form in a sample gradually decreases, some of the diffraction peaks attributed to the crystal form in its X-ray powder diffraction pattern may become less due to the detection sensitivity of the instrument.
术语“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的强度与第一强峰的强度的比值。The term "relative intensity" refers to a ratio of the intensity of the other peak to the intensity of the first strong peak when the intensity of the first strong peak in a group of diffraction peaks belonging to a certain crystal form is defined as 100%.
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。In the context of the present invention, the values of 2θ (also known as 2theta or diffraction peak) in the X-ray powder diffraction pattern are all in degrees (°).
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。When referring to the spectrum and / or data in the figure, the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
所述晶体的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。The X-ray powder diffraction peak of the crystal, the measurement of the 2θ or diffraction peak of its X-ray powder diffraction pattern has experimental errors, between one machine and another machine, and between one sample and another sample, The measurement of the 2θ or diffraction peak of the X-ray powder diffraction pattern may be slightly different, and the value of the experimental error or difference may be +/- 0.2 units or +/- 0.1 units or +/- 0.05 units, Therefore, the value of the 2θ or diffraction peak cannot be regarded as absolute.
所述晶体的差示扫描量热曲线(DSC)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。The differential scanning calorimetry curve (DSC) of the crystal has experimental errors. The position and peak of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample. The value of the experimental error or difference may be 5 ° C or lower, or 4 ° C or lower, or 3 ° C or lower, or 2 ° C or lower, or 1 ° C or lower. Therefore, the peak position or Values cannot be considered absolute.
所述晶体的热重分析曲线(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热曲线或失重率可能会略有差别，实验误差或差别的数值可能小于等于0.004％或0.003％或0.002％或0.001％，因此所述热重分析曲线或其失重率不能视为绝对的。There is an experimental error in the thermogravimetric analysis curve (TGA) of the crystal. The endothermic curve or weight loss rate may be slightly different between one machine and another, and between one sample and another. The experimental error Or the difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as absolute.
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个 数字的数值有可能会出现1％，2％，或5％等差异。当大约用来形容X-射线粉末衍射峰的2θ(又称2theta或衍射峰)值时，大约表示所述2θ值可能有+/-0.2个单位或+/-0.1个单位或+/-0.05个单位差异。In the context of the present invention, all numbers disclosed herein are approximate, whether or not the words "about" or "about" are used. The value of each digit may vary by 1%, 2%, or 5%. When used to describe a 2θ (also known as 2theta or diffraction peak) value of an X-ray powder diffraction peak, it roughly indicates that the 2θ value may have +/- 0.2 units or +/- 0.1 units or +/- 0.05 Unit difference.
“室温”是指温度在大约20℃-35℃或大约23℃-28℃或大约25℃。"Room temperature" means a temperature between about 20 ° C and 35 ° C or about 23 ° C and 28 ° C or about 25 ° C.
术语“良溶剂”可以是单一溶剂或混合溶剂，指式(X)所示的化合物在该单一溶剂或混合溶剂中的溶解度大于1g/L,或大于2g/L,或大于3g/L,或大于4g/L,或大于5g/L,或大于6g/L,或大于7g/L,或大于8g/L,或大于9g/L,或大于10g/L,或大于15g/L,或大于20g/L,或大于30g/L,或大于40g/L,或大于50g/L,或大于60g/L,或大于70g/L,或大于80g/L,或大于100g/L。在一些实施例中，式(X)所示的化合物在良溶剂中的溶解度比不良溶剂大；在一些实施例中，良溶剂和不良溶剂对式(X)所示的化合物的溶解度之差大约为10％,20％,30％,40％,50％,60％,70％,80％或90％；在一些实施例中，良溶剂对式(X)所示的化合物的溶解度比不良溶剂大，大于10％,20％,30％,40％,50％,60％,70％,80％或90％。The term “good solvent” may be a single solvent or a mixed solvent, and means that the compound represented by formula (X) has a solubility in the single solvent or mixed solvent of greater than 1 g / L, or greater than 2 g / L, or greater than 3 g / L, or Greater than 4g / L, or greater than 5g / L, or greater than 6g / L, or greater than 7g / L, or greater than 8g / L, or greater than 9g / L, or greater than 10g / L, or greater than 15g / L, or greater than 20g / L, or greater than 30g / L, or greater than 40g / L, or greater than 50g / L, or greater than 60g / L, or greater than 70g / L, or greater than 80g / L, or greater than 100g / L. In some embodiments, the solubility of the compound represented by formula (X) in a good solvent is greater than that of the poor solvent; in some embodiments, the difference between the solubility of the good solvent and the poor solvent for the compound represented by the formula (X) is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, the solubility of a good solvent for a compound represented by formula (X) is less than that of a poor solvent Large, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
发明详述Detailed description of the invention
第一方面，发明人通过研究开发了式(X)所示的化合物和异烟碱形成的共晶体In the first aspect, the inventors have developed a co-crystal formed by a compound represented by formula (X) and isonicotine through research.
Figure PCTCN2019100468-appb-000002
Figure PCTCN2019100468-appb-000002
式(X)所示的化合物和异烟碱形成的共晶体，具有如下特性：式(X)所示的化合物和异烟碱以1：1摩尔比存在。A co-crystal formed by a compound represented by the formula (X) and isonicotinoid has the following characteristics: the compound represented by the formula (X) and isoniatin exist in a 1: 1 molar ratio.
式(X)所示的化合物和异烟碱形成的共晶体，具有如下特性：其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、19.5、21.1、22.6、24.5和/或27.3度的位置有峰。The co-crystal formed by the compound represented by formula (X) and isonicotinoid has the following characteristics: the X-ray powder diffraction pattern thereof at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 19.5, 21.1, 22.6, 24.5, and / Or there is a peak at 27.3 degrees.
式(X)所示的化合物和异烟碱形成的共晶体，具有如下特性：其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、22.6、24.5和/或27.3度的位置有峰。The co-crystals formed by the compound represented by formula (X) and isonicotinoid have the following characteristics: the X-ray powder diffraction pattern thereof at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1 There are peaks at, 22.6, 24.5, and / or 27.3 degrees.
一些实施例中，共晶体的X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、22.6、22.9、24.1、24.5、27.3和30.6度的位置的一处或多处有峰。In some embodiments, the X-ray powder diffraction pattern of the eutectic at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 22.6, 22.9, 24.1, 24.5, 27.3, and 30.6 degrees. There are peaks at one or more locations.
一些实施例中，共晶体的X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、21.9、22.6、22.9、23.7、24.1、24.5、26.5、27.3、30.2和30.6度的位置的一处或多处有峰。一些实施例中，共晶体的X-射线粉末衍射图如图1所示，其中，在2θ大约为22.60度的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。In some embodiments, the X-ray powder diffraction pattern of the co-crystal at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 21.9, 22.6, 22.9, 23.7, 24.1, 24.5, 26.5 There are peaks at one or more of the positions of 27.3, 30.2, and 30.6 degrees. In some embodiments, the X-ray powder diffraction pattern of the co-crystal is shown in FIG. 1, wherein the relative intensity of the peak at 2θ of about 22.60 degrees is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%. %, Or greater than 99%.
所述的共晶体，还具有如下特性：其差示扫描量热曲线(DSC)在约100℃-150℃处具有吸热峰。在一具体实施方式中，所述的共晶体差示扫描量热曲线(DSC)在约125℃-150℃处具有吸热峰，在一具体实施方式中，所述的共晶体差示扫描量热曲线(DSC)在约130℃-140℃处具有吸热峰，吸热峰峰顶值为约138℃。在一些实施方式中，所述的共晶体的差示扫描量热曲线(DSC)如图2所示。The eutectic also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at about 100 ° C to 150 ° C. In a specific embodiment, the eutectic differential scanning calorimetry curve (DSC) has an endothermic peak at about 125 ° C-150 ° C. In a specific embodiment, the eutectic differential scanning quantity The thermal curve (DSC) has an endothermic peak at about 130 ° C-140 ° C, and the peak end value of the endothermic peak is about 138 ° C. In some embodiments, the differential scanning calorimetry (DSC) of the eutectic is shown in FIG. 2.
所述的共晶体热重分析曲线(TGA)在约30℃-150℃处具有小于2％的失重。在一具体实施方式中，所述的共晶体热重分析曲线(TGA)在约30℃-150℃处具有小于1.05％的失重；在一具体实施方式中，所述的共晶体热重分析曲线(TGA)如图3所示。The eutectic thermogravimetric analysis curve (TGA) has a weight loss of less than 2% at about 30 ° C to 150 ° C. In a specific embodiment, the eutectic thermogravimetric analysis curve (TGA) has a weight loss of less than 1.05% at about 30 ° C to 150 ° C; in a specific embodiment, the eutectic thermogravimetric analysis curve (TGA) is shown in Figure 3.
所述式(X)所示的化合物和异烟碱形成的共晶体为具有良好外观和流动性的粉末，在溶出度、流动性等方面具有良好的性能，有利于储存、转移、生产工艺中操作，适于制备成其药用组合物。The co-crystal formed by the compound represented by formula (X) and isonicotinoid is a powder with good appearance and fluidity, and has good properties in terms of dissolution, fluidity, etc., which is beneficial to storage, transfer and production processes. It is suitable for preparation into a pharmaceutical composition.
所述式(X)所示的化合物和异烟碱形成的共晶体稳定，溶解性好，可以用于制备治疗肺动脉高压(PAH)等疾病的药物制剂，或用于制备抑制血管平滑肌细胞增殖或抑制血小板聚集的药物制剂。The co-crystals formed by the compound represented by the formula (X) and isonicotinoid are stable and have good solubility, and can be used for preparing pharmaceutical preparations for treating diseases such as pulmonary hypertension (PAH), or for inhibiting the proliferation of vascular smooth muscle cells or Pharmaceutical preparations that inhibit platelet aggregation.
第二方面，本发明提供了所述的共晶体的制备方法。In a second aspect, the present invention provides a method for preparing the co-crystal.
一种制备式(X)所示的化合物和异烟碱形成的共晶体的方法，包括：将(X)所示的化合物和异烟碱溶于良溶剂中，室温下挥发除去溶剂，得到所述的共晶体。A method for preparing a co-crystal formed by a compound represented by the formula (X) and isoniatin, comprising: dissolving the compound represented by the formula (X) and isoniatin in a good solvent, volatilizing the solvent at room temperature to obtain The co-crystals described above.
在一些实施例中，所述的方法中，所述良溶剂为低级脂肪族醇。In some embodiments, in the method, the good solvent is a lower aliphatic alcohol.
在一些实施例中，所述的方法中，所述低级脂肪族醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、叔丁醇中的一种或多种。在一些实施方式中，所述良溶剂为甲醇或乙醇或其组合。In some embodiments, in the method, the lower aliphatic alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and t-butanol. Or more. In some embodiments, the good solvent is methanol or ethanol or a combination thereof.
在一些实施例中，所述的共晶体的制备方法包括：将式(X)所示的化合物和异烟碱完全溶于良溶剂中，室温下基本挥干溶剂，然后真空干燥至恒重，得到所述的共晶体。在一些实施例中，所述的共晶体的制备方法包括：将式(X)所示的化合物和异烟碱完全溶于良溶剂中，室温下基本挥干溶剂，50℃真空干燥24小时，得到所述的共晶体。In some embodiments, the method for preparing the co-crystals includes: completely dissolving the compound represented by formula (X) and isonicotinoid in a good solvent, basically drying the solvent at room temperature, and then vacuum drying to constant weight, The co-crystal is obtained. In some embodiments, the method for preparing the co-crystals includes: completely dissolving the compound represented by formula (X) and isonicotinoid in a good solvent, basically drying the solvent at room temperature, and vacuum drying at 50 ° C for 24 hours. The co-crystal is obtained.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1示实施例1所得的式(X)所示的化合物和异烟碱形成的共晶体的X-射线粉末衍射图。FIG. 1 shows an X-ray powder diffraction pattern of a co-crystal formed by the compound represented by the formula (X) obtained in Example 1 and isoniatin.
图2示实施例1所得的式(X)所示的化合物和异烟碱形成的共晶体的差示扫描热曲线(DSC)。FIG. 2 shows a differential scanning thermal curve (DSC) of a co-crystal formed from the compound represented by the formula (X) obtained in Example 1 and isoniatin.
图3示实施例1所得的式(X)所示的化合物和异烟碱形成的共晶体热重分析图(TGA)。FIG. 3 shows a thermogravimetric analysis chart (TGA) of a co-crystal formed from the compound represented by the formula (X) obtained in Example 1 and isonicotinoid.
图4示实施例5中(X)的化合物和异烟碱形成的共晶体的X-射线粉末衍射图。FIG. 4 shows an X-ray powder diffraction pattern of a co-crystal formed by the compound (X) and isonicotinoid in Example 5. FIG.
图5示实施例5中(X)的化合物和异烟碱形成的共晶体的差示扫描热曲线(DSC)。FIG. 5 shows a differential scanning thermal curve (DSC) of a co-crystal formed by the compound (X) and isonicotinoid in Example 5. FIG.
图6示实施例5中(X)的化合物游离酸的X-射线粉末衍射图。FIG. 6 shows an X-ray powder diffraction pattern of the free acid of the compound of (X) in Example 5. FIG.
图7示实施例5中(X)的化合物游离酸的差示扫描热曲线(DSC)。FIG. 7 shows a differential scanning thermal curve (DSC) of a compound's free acid in (X) in Example 5. FIG.
具体实施方式detailed description
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention are all commercially available or can be prepared by the method described in the present invention.
本发明中，mg表示毫克，mL表示毫升，rpm表示转/每分钟，h表示小时。In the present invention, mg means milligram, mL means milliliter, rpm means revolutions per minute, and h means hour.
仪器参数Instrument parameters
除非参数中另行规定，以下所有分析都在室温下进行。Unless otherwise specified in the parameters, all of the following analyses were performed at room temperature.
粉末X-射线衍射(XRPD)研究X-ray powder diffraction (XRPD) study
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2019100468-appb-000003
1.540598；Kα2
Figure PCTCN2019100468-appb-000004
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为6.6mm.采用θ-θ连续扫描模式，得到3°～60°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0167°的扫描步长在3～60°2θ±0.2°范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。 X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3 * 15 zero background sample holder for a transflective sample stage. The radiation source used is (Cu, kα, Kα1
Figure PCTCN2019100468-appb-000003
1.540598; Kα2
Figure PCTCN2019100468-appb-000004
1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40mA. The beam divergence of X-rays, which is the effective size of the X-ray constraint on the sample, is 6.6mm. θ continuous scan mode, the effective 2θ range of 3 ° ~ 60 ° is obtained. Take an appropriate amount of sample at the circular groove of the zero background sample holder under ambient conditions (approximately 18 ° C to 32 ° C), press gently with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The traditional XRPD pattern was generated by scanning the sample at a step size of 0.0167 ° in the range of 3 to 60 ° 2θ ± 0.2 °. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data Viewer and HighScore Plus.
差示扫描量热法(DSC)Differential scanning calorimetry (DSC)
DSC测量在TA InstrumentsTM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在30℃到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。DSC measurements were performed in a TA Instruments Model Q2000 using a sealed disc device. The sample (about 1 to 3 mg) was weighed in an aluminum pan, capped with Tzero, accurately recorded to one hundredth of a milligram, and the sample was transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL / min. Data were collected between 30 ° C and 300 ° C at a heating rate of 10 ° C / min. The endothermic peak was plotted downward, and the data was analyzed and displayed by TA Universal Analysis.
热重分析法(TGA)Thermogravimetric analysis (TGA)
在TA Instruments Q500上采集TGA数据。使用认证的镍校准仪器的温度。通常将8-12mg样品加载到预称重的铂金坩埚上，并以10℃/min从30℃加热至300℃。在样品上方保持60mL/min的氮气清扫。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示失重的百分含量(Weight(％))。Collect TGA data on TA Instruments Q500. Use a certified nickel to calibrate the temperature of the instrument. A 8-12 mg sample is usually loaded on a pre-weighed platinum crucible and heated from 30 ° C to 300 ° C at 10 ° C / min. Maintain a nitrogen sweep of 60 mL / min over the sample. In the TGA graph, the abscissa represents temperature (Temperature, ° C), and the ordinate represents the percentage content of weight loss (Weight (%)).
实施例1 制备共晶体Example 1 Preparation of co-crystals
5mL PE管中加入43.2mg Ralinepag、12.2mg异烟碱和2.0mL乙醇溶剂，磁力搅拌250rpm，室温(约28.0℃)下固体完全溶解形成溶液。溶液室温自然挥发约3天，溶剂基本挥发干，50℃真空干燥24h得到白色固体约55.0mg。检测，为Ralinepag/异烟碱共晶体，其X射线粉末衍射图谱与图1基本一致，其DSC、TGA图谱分别与图2、3基本一致。In a 5 mL PE tube, 43.2 mg of Ralinepag, 12.2 mg of isoniatin and 2.0 mL of ethanol were added, and magnetic stirring was performed at 250 rpm. The solid was completely dissolved at room temperature (about 28.0 ° C) to form a solution. The solution naturally volatilized at room temperature for about 3 days, and the solvent was basically evaporated to dryness, and dried under vacuum at 50 ° C for 24 h to obtain about 55.0 mg of a white solid. The X-ray powder diffraction pattern of Ralinepag / isonicotine co-crystal was basically the same as that in Figure 1, and the DSC and TGA spectra were basically the same as those in Figures 2 and 3, respectively.
实施例2 制备共晶体Example 2 Preparation of co-crystals
10mL PE管中加入129.6mg Ralinepag、36.6mg异烟碱和6.0mL乙醇溶剂，磁力搅拌250rpm，室温(约28.0℃)下固体完全溶解形成溶液。溶液室温自然挥发约5天，溶剂基本挥发干，50℃真空干燥24h得到白色固体约165.1mg，经测定为Ralinepag/异烟碱共晶体，其X射线粉末衍射图谱与图1基本一致，其DSC、TGA图谱分别与图2、3基本一致。In a 10 mL PE tube, 129.6 mg of Ralinepag, 36.6 mg of isoniatin and 6.0 mL of ethanol were added, and magnetic stirring was performed at 250 rpm. The solid was completely dissolved at room temperature (about 28.0 ° C) to form a solution. The solution naturally volatilized at room temperature for about 5 days. The solvent was basically evaporated to dryness. Drying at 50 ° C under vacuum for 24 hours gave about 165.1 mg of a white solid. It was determined to be Ralinepag / isonicotine co-crystal. Its X-ray powder diffraction pattern was basically the same as that in Figure 1. Its DSC The TGA spectrum is basically consistent with Figures 2 and 3, respectively.
实施例3 制备共晶体Example 3 Preparation of co-crystals
5mL PE管中加入43.2mg Ralinepag、12.2mg异烟碱和2.0mL乙醇溶剂，磁力搅拌250rpm，室温(约28.0℃)下固体完全溶解形成溶液。溶液室温自然挥发约2天，溶剂基本挥发干，50℃真空干燥24h得到白色固体约54.5mg，经测定为Ralinepag/异烟碱共晶体，其X射线粉末衍射图谱与图1基本一致，其DSC、TGA图谱分别与图2、3基本一致。In a 5 mL PE tube, 43.2 mg of Ralinepag, 12.2 mg of isoniatin and 2.0 mL of ethanol were added, and magnetic stirring was performed at 250 rpm. The solid was completely dissolved at room temperature (about 28.0 ° C) to form a solution. The solution was naturally volatilized at room temperature for about 2 days. The solvent was basically evaporated to dryness. Drying at 50 ° C under vacuum for 24 hours gave about 54.5 mg of a white solid. It was determined to be a Ralinepag / isonicotine co-crystal. The TGA spectrum is basically consistent with Figures 2 and 3, respectively.
实施例4 制备共晶体Example 4 Preparation of co-crystals
10mL PE管中加入129.6mg Ralinepag、36.6mg异烟碱和6.0mL甲醇溶剂，磁力搅拌250rpm，室温(约28.0℃)下固体完全溶解形成溶液。溶液室温自然挥发约3天，溶剂基本挥发干，50℃真空干燥24h得到白色固体约165.5mg，经测定为Ralinepag/异烟碱共晶体，其X射线粉末衍射图谱与图1基本一致，其DSC、TGA图谱分别与图2、3基本一致。A 10mL PE tube was charged with 129.6mg of Ralinepag, 36.6mg of isonicotinoid and 6.0mL of methanol solvent, magnetically stirred at 250rpm, and the solid was completely dissolved at room temperature (about 28.0 ° C) to form a solution. The solution was naturally volatilized at room temperature for about 3 days. The solvent was basically evaporated to dryness. Vacuum drying at 50 ° C for 24 h gave about 165.5 mg of a white solid. It was determined to be Ralinepag / isonicotine co-crystal. The TGA spectrum is basically consistent with Figures 2 and 3, respectively.
实施例5 稳定性测试Example 5 stability test
根据药物制剂稳定性试验指导原则，对Ralinepag/异烟碱共晶体和Ralinepag游离酸晶型(专利申请WO 2009117095 A1中的图27公开的Ralinepag游离酸晶型)进行影响因素实验，包括高温试验、高湿试验和强光照射试验，考察影响其晶型的稳定性条件，如下表1所示。According to the guidelines for the stability test of pharmaceutical preparations, Ralinepag / isonicotine co-crystals and Ralinepag free acid crystalline forms (Paline application disclosed in Figure 27 of the Ralinepag free acid crystalline form in patent application WO 2009117095 A1) were subjected to influencing factor experiments, including high temperature tests, The high humidity test and strong light irradiation test are used to investigate the conditions that affect the stability of its crystal form, as shown in Table 1 below.
高温试验：分别取Ralinepag/异烟碱共晶体和Ralinepag游离酸晶型样品适量，平铺置称量瓶中，在60±5℃、RH75±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约10mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况，结果见图4-7。High temperature test: Take appropriate amounts of Ralinepag / isonicotine co-crystals and Ralinepag free acid crystalline samples, place them in a weighing bottle, place them in a 60 ± 5 ℃, RH75 ± 5% constant temperature and humidity box, and place them in 0 About 10 mg of the above sample was taken on days 5, 5 and 15 and its crystal form was tested by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The results are shown in Figure 4-7.
高湿试验：分别取Ralinepag/异烟碱共晶体和Ralinepag游离酸晶型样品适量，平铺置称量瓶中，在25℃、RH92.5±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约10mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况，结果见图4-7。High humidity test: Take appropriate amounts of Ralinepag / isonicotine co-crystals and Ralinepag free acid crystal form samples, place them in a weighing bottle, place them in a 25 ° C, RH92.5 ± 5% constant temperature and humidity box, and place them in About 0 mg of the above sample was taken on 0, 5 and 15 days, and its crystal form was tested by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The results are shown in Figure 4-7.
光照试验：分别取Ralinepag/异烟碱共晶体和Ralinepag游离酸晶型样品适量，平铺至称量瓶中，在可见光4500Lux±500Lux(VIS)、紫外光1.7W*h/m2(UV)的恒温恒湿箱(25℃、RH60％±5％)条件下放置，然后分别于0、5和15天取上述样品约10mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况，结果见图4-7。Light test: Take appropriate amounts of Ralinepag / isonicotine co-crystal and Ralinepag free acid crystalline sample, and flatten them into a weighing bottle. In the visible light 4500Lux ± 500Lux (VIS), ultraviolet light 1.7W * h / m2 (UV) Place in a constant temperature and humidity box (25 ° C, RH60% ± 5%), and then take about 10 mg of the above sample on 0, 5 and 15 days, respectively, using powder X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) test its crystal form, the results are shown in Figure 4-7.
表1.Ralinepag/异烟碱共晶体、Ralinepag游离酸晶型的稳定性试验条件Table 1. Stability test conditions of Ralinepag / isonicotin co-crystal and Ralinepag free acid crystal form
Figure PCTCN2019100468-appb-000005
Figure PCTCN2019100468-appb-000005
结论：Ralinepag/异烟碱共晶体与Ralinepag游离酸晶型样品在高温、高湿和光照三个影响因素试验条件下的粉末X-射线衍射(XRPD)、差示扫描量热法(DSC)图谱结果表明Ralinepag/异烟碱共晶体与Ralinepag游离酸晶型均具有良好的稳定性。Conclusion: The powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC) spectra of Ralinepag / isonicotine co-crystal and Ralinepag free acid crystalline samples under the conditions of high temperature, high humidity and light are tested. The results show that both Ralinepag / isonicotin co-crystals and Ralinepag free acid crystal form have good stability.
实施例6 溶解度测试Example 6 Solubility Test
预先称重烧瓶和搅拌子，精确称取Ralinepag/异烟碱共晶体或Ralinepag游离酸晶型样品，分别加入瓶中，滴加水，相同方式搅拌，至固体溶解停止加水。无目视可见的颗粒时，视为完全溶解。溶解后称重试管、搅拌子、和水溶液的总重量，计算出所加水的重量，然后计算出溶解度；水的密度按照1.00g/mL计算，分别测试这两种晶型样品在25℃或37℃的水中的溶解度，溶解度测试实验结果见表2。Weigh the flask and stirrer in advance, accurately weigh Ralinepag / isonicotine co-crystals or Ralinepag free acid crystalline samples, add them to the bottle, add water dropwise, and stir in the same way until the solids are dissolved and stop adding water. When there are no visible particles, it is considered to be completely dissolved. After dissolution, weigh the total weight of the test tube, stirrer, and aqueous solution, calculate the weight of the water added, and then calculate the solubility; the density of the water is calculated according to 1.00g / mL, and the two crystal form samples are tested at 25 ° C or 37 ° C. The solubility in water, the experimental results of the solubility test are shown in Table 2.
表2.Ralinepag/异烟碱共晶体和Ralinepag游离酸晶型的溶解度测试实验结果Table 2. Solubility test results of Ralinepag / isonicotin co-crystals and Ralinepag free acid crystal form
温度temperature 晶型Crystal form 溶解度Solubility
25.0℃25.0 ℃ Ralinepag游离酸晶型Ralinepag Free Acid Crystal Form 0.010mg/mL0.010mg / mL
25.0℃25.0 ℃ Ralinepag/异烟碱共晶体Ralinepag / isonicotine co-crystal 0.102mg/mL0.102mg / mL
37.0℃37.0 ℃ Ralinepag游离酸晶型Ralinepag Free Acid Crystal Form 0.019mg/mL0.019mg / mL
37.0℃37.0 ℃ Ralinepag/异烟碱共晶体Ralinepag / isonicotine co-crystal 0.282mg/mL0.282mg / mL
结论：Ralinepag/异烟碱共晶体的溶解度显著高于Ralinepag游离酸晶型的溶解度。Conclusion: The solubility of Ralinepag / isonicotine co-crystals is significantly higher than the solubility of Ralinepag free acid crystalline form.
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。The method of the present invention has been described through the preferred embodiments, and it is obvious that relevant persons can modify or appropriately modify and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. . Those skilled in the art can learn from the content of this article and appropriately improve the process parameter implementation. In particular, it should be noted that all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present invention.

Claims (12)

  1. 一种式(X)所示的化合物和异烟碱形成的共晶体A co-crystal formed by a compound of formula (X) and isonicotinoid
    Figure PCTCN2019100468-appb-100001
    Figure PCTCN2019100468-appb-100001
  2. 根据权利要求1所述的共晶体，其中式(X)所示的化合物和异烟碱以1：1摩尔比存在。The co-crystal according to claim 1, wherein the compound represented by the formula (X) and isoniatin are present in a 1: 1 molar ratio.
  3. 根据权利要求1所述的共晶体，其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、19.5、21.1、22.6、24.5、27.3度的位置有峰。The eutectic according to claim 1, wherein the X-ray powder diffraction pattern has peaks at positions where 2θ is approximately 6.8, 10.1, 15.1, 16.9, 19.5, 21.1, 22.6, 24.5, 27.3 degrees.
  4. 根据权利要求1所述的共晶体，其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、22.6、24.5、27.3度的位置有峰。The eutectic according to claim 1, wherein the X-ray powder diffraction pattern has peaks at positions where 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 22.6, 24.5, 27.3 degrees. .
  5. 根据权利要求1所述的共晶体，其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、22.6、22.9、24.1、24.5、27.3、30.6度的位置有峰。The eutectic according to claim 1, wherein the X-ray powder diffraction pattern at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 22.6, 22.9, 24.1, 24.5, 27.3, There is a peak at 30.6 degrees.
  6. 根据权利要求1所述的共晶体，其X-射线粉末衍射图中在2θ大约为6.8、10.1、15.1、16.9、17.6、18.1、18.9、19.5、21.1、21.9、22.6、22.9、23.7、24.1、24.5、26.5、27.3、30.2、30.6度的位置有峰。The eutectic according to claim 1, wherein the X-ray powder diffraction pattern at 2θ is approximately 6.8, 10.1, 15.1, 16.9, 17.6, 18.1, 18.9, 19.5, 21.1, 21.9, 22.6, 22.9, 23.7, 24.1, There are peaks at 24.5, 26.5, 27.3, 30.2, and 30.6 degrees.
  7. 根据权利要求1所述的共晶体，其X-射线粉末衍射图基本上如图1所示。The X-ray powder diffraction pattern of the eutectic according to claim 1 is substantially as shown in FIG.
  8. 根据权利要求1所述的共晶体，其差示扫描量热曲线在约100℃-150℃处具有吸热峰。The eutectic according to claim 1, wherein the differential scanning calorimetry curve has an endothermic peak at about 100 ° C to 150 ° C.
  9. 一种组合物，其包含权利要求1-8任一所述的共晶体和药学上可接受的载体。A composition comprising the co-crystal of any one of claims 1-8 and a pharmaceutically acceptable carrier.
  10. 一种制备权利要求1-8任一所述的共晶体的方法，包括：将式(X)的化合物和异烟碱溶于良溶剂中，室温下挥发除去溶剂，得到所述的共晶体。A method for preparing the co-crystal according to any one of claims 1 to 8, comprising: dissolving a compound of formula (X) and isoniatin in a good solvent, and volatilizing and removing the solvent at room temperature to obtain the co-crystal.
  11. 根据权利要求10所述的方法，所述良溶剂为低级脂肪族醇。The method according to claim 10, wherein the good solvent is a lower aliphatic alcohol.
  12. 根据权利要求11所述的方法，所述低级脂肪族醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、叔丁醇中的至少一种。The method according to claim 11, wherein the lower aliphatic alcohol is at least one selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.
PCT/CN2019/100468 2018-09-06 2019-08-14 Pharmaceutical cocrystal and preparation method therefor WO2020048299A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980057194.XA CN112638865B (en) 2018-09-06 2019-08-14 Pharmaceutical co-crystals and process for their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811037836 2018-09-06
CN201811037836.3 2018-09-06

Publications (1)

Publication Number Publication Date
WO2020048299A1 true WO2020048299A1 (en) 2020-03-12

Family

ID=69722993

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/100468 WO2020048299A1 (en) 2018-09-06 2019-08-14 Pharmaceutical cocrystal and preparation method therefor

Country Status (2)

Country Link
CN (1) CN112638865B (en)
WO (1) WO2020048299A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023158634A1 (en) * 2022-02-15 2023-08-24 United Therapeutics Corporation Crystalline prostacyclin (ip) receptor agonist and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117095A1 (en) * 2008-03-18 2009-09-24 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2480526A1 (en) * 2009-09-23 2012-08-01 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of pgi2 receptor agonists
CN102503886B (en) * 2011-10-11 2013-09-11 中山大学 Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof
CN106986868B (en) * 2016-01-21 2020-04-21 广东东阳光药业有限公司 Co-crystals comprising apixaban and methods of making the same
CN107445942A (en) * 2016-05-31 2017-12-08 广东东阳光药业有限公司 R-lansoprazole eutectic and preparation method thereof
KR20230021186A (en) * 2016-11-10 2023-02-13 아레나 파마슈티칼스, 인크. Methods of treating pah with combinations of ralinepag and other agents
CN110903219A (en) * 2018-09-18 2020-03-24 广东东阳光药业有限公司 Salt of amide derivative and process for producing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117095A1 (en) * 2008-03-18 2009-09-24 Arena Pharmaceuticals, Inc. Modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN JIA-MEI ET AL: "Application of Supramolecular Chemistry on Pharmaceutical Cocrystals", CHEMICAL JOURNAL OF CHINESE UNIVERSITIES, vol. 32, no. 9, 30 September 2011 (2011-09-30), pages 2004 - 2005, XP055690569 *
TRAN, T. A. ET AL: "Discovery of 2‑(((1r,4r)‑4-(((4- Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy) acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 3, 10 January 2017 (2017-01-10), pages 913 - 927, XP002781144 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023158634A1 (en) * 2022-02-15 2023-08-24 United Therapeutics Corporation Crystalline prostacyclin (ip) receptor agonist and uses thereof

Also Published As

Publication number Publication date
CN112638865B (en) 2022-07-26
CN112638865A (en) 2021-04-09

Similar Documents

Publication Publication Date Title
US10669275B2 (en) Methods of preparing co-crystals of ibrutinib with carboxylic acids
TWI285635B (en) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition
WO2021056850A1 (en) Eutectic crystal formed by apixaban and carboxylic acid, and preparation method therefor
WO2021129589A1 (en) New crystal form of kd-025 and preparation method therefor
JP7358466B2 (en) Salts of LSD1 inhibitors and their crystal forms
WO2023040513A1 (en) Crystal form of amg510 compound, and preparation method therefor and use thereof
CZ201584A3 (en) Ibrutinib sulfate salt
JP2006528202A (en) Levalbuterol hydrochloride polymorph B
WO2020048299A1 (en) Pharmaceutical cocrystal and preparation method therefor
WO2021104022A1 (en) Novel crystalline form of tropifexor and preparation method therefor
WO2021104021A1 (en) New crystal form of tropifexor and preparation method therefor
WO2021057834A1 (en) Crystal form of ester compound and preparation method therefor
TWI378929B (en) Crystalline 1h-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1h-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses
CN110903219A (en) Salt of amide derivative and process for producing the same
WO2013075669A1 (en) Crystal and amorphous substance of dapoxetine hydrochloride and preparation method therefor
WO2016157136A1 (en) Crystalline forms of idelalisib
CN107663166A (en) Lome Tapai and its production and use
US20200255435A1 (en) Salts and solid state forms of larotrectinib
CN117003702B (en) Fluocytosine-orotate and preparation method and application thereof
WO2023274040A1 (en) Crystal form of triazolopyridine-substituted indazole compound and preparation method therefor
WO2017028762A1 (en) Crystal form of naphthalene cyclic compound
WO2023143079A1 (en) Crystal form of compound and preparation method therefor
TWI727517B (en) Beraprost-314d crystals and methods for preparation thereof
WO2022048613A1 (en) Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method therefor
US20230265074A1 (en) Solid forms of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

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: 19856829

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: 19856829

Country of ref document: EP

Kind code of ref document: A1