WO2020048299A1 - Co-cristal pharmaceutique et son procédé de préparation - Google Patents

Co-cristal pharmaceutique et son procédé de préparation Download PDF

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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
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WIPO (PCT)
Prior art keywords
crystal
ralinepag
ray powder
powder diffraction
diffraction pattern
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PCT/CN2019/100468
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English (en)
Chinese (zh)
Inventor
张�杰
陈勇
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN201980057194.XA priority Critical patent/CN112638865B/zh
Publication of WO2020048299A1 publication Critical patent/WO2020048299A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—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

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine technique de l'ingénierie pharmaceutique et chimique et concerne principalement un co-cristal pharmaceutique et son procédé de préparation. Le co-cristal pharmaceutique est formé de ralinepag et d'isonicotine et présente les avantages d'avoir une bonne stabilité et une solubilité élevée et d'être approprié pour préparer une composition pharmaceutique.
PCT/CN2019/100468 2018-09-06 2019-08-14 Co-cristal pharmaceutique et son procédé de préparation WO2020048299A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023158634A1 (fr) * 2022-02-15 2023-08-24 United Therapeutics Corporation Agoniste du récepteur de prostacycline (ip) cristalline et ses utilisations

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WO2009117095A1 (fr) * 2008-03-18 2009-09-24 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de la prostacycline (pgi2) utiles pour le traitement de troubles liés à celui-ci

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EP2480526A1 (fr) * 2009-09-23 2012-08-01 Arena Pharmaceuticals, Inc. Formes cristallines et procédés pour la préparation d'agonistes du récepteur pgi2
CN102503886B (zh) * 2011-10-11 2013-09-11 中山大学 阿戈美拉汀-异烟碱共晶及其组合物和制备方法
CN106986868B (zh) * 2016-01-21 2020-04-21 广东东阳光药业有限公司 包含阿哌沙班的共晶体及其制备方法
CN107445942A (zh) * 2016-05-31 2017-12-08 广东东阳光药业有限公司 右兰索拉唑共晶及其制备方法
WO2018089804A1 (fr) * 2016-11-10 2018-05-17 Arena Pharmaceuticals, Inc. Méthodes de traitement de l'htap à l'aide de combinaisons de ralinepag et d'autres agents
CN110903219A (zh) * 2018-09-18 2020-03-24 广东东阳光药业有限公司 酰胺衍生物的盐及其制备方法

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WO2009117095A1 (fr) * 2008-03-18 2009-09-24 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de la prostacycline (pgi2) utiles pour le traitement de troubles liés à celui-ci

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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 (fr) * 2022-02-15 2023-08-24 United Therapeutics Corporation Agoniste du récepteur de prostacycline (ip) cristalline et ses utilisations

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