CN110240562B - Medicinal salt and crystal form of prolyl hydroxylase inhibitor and preparation method thereof - Google Patents
Medicinal salt and crystal form of prolyl hydroxylase inhibitor and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a medicinal salt and a crystal form of a prolyl hydroxylase inhibitor and a preparation method thereof. In particular to a pharmaceutically acceptable salt and a crystal form of a compound shown as a formula (I) and a preparation method thereof. The new medicinal salt and the new crystal form have good stability and can be better used for clinical treatment.
Description
Technical Field
The invention relates to pharmaceutically acceptable salts and crystal forms of alkynyl pyridine prolyl hydroxylase inhibitors, and a preparation method and application thereof in preparing medicaments for treating prolyl hydroxylase mediated diseases.
Background
Anemia generally refers to any abnormality of hemoglobin or red blood cells that results in a reduction in the level of oxygen in the blood. Anemia can also occur in association with chronic infections, neoplastic diseases, chronic inflammation, and other chronic diseases including pathologies that subsequently undergo inflammatory inhibition of the bone marrow. Anemia of chronic disease is one of the most common syndromes in the medical field, such as anemia of chronic kidney disease. The primary cause of anemia of chronic kidney disease is hyposecretion of Erythropoietin (EPO) (Nephrol Dial Transplant 17(2002) 2-7). Insufficient EPO secretion can hinder the production of red blood cells, resulting in the development of anemia. Expression and secretion of EPO is regulated by the transcription factor Hypoxia Inducible Factor (HIF). HIF proteins with intact transcriptional function consist of two subunits, HIF- α and HIF- β, where the HIF- α subunit is regulated by Prolyl Hydroxylase (PHD), which hydroxylates HIF- α and thereby promotes its degradation. In humans, prolyl hydroxylase 2(PHD2) (Journal of Medicinal Chemistry 56(2013)9369-9402) is the most prominent subtype in regulating HIF levels. When the activity of Proline Hydroxylase (PHD) in vivo is inhibited, HIF-alpha subunit in vivo can be stabilized, so that the HIF-alpha subunit enters the nucleus and is combined with HIF-beta subunit in the nucleus to form stable HIF dimer, and further the expression of downstream genes is caused, thereby promoting the expression and secretion of EPO. Therefore, inhibiting the activity of prolyl hydroxylase can increase the level of HIF-alpha and increase the production of EPO, thereby promoting the maturation of erythrocytes, improving the ability of blood to transport oxygen and improving anemia or ischemia.
WO2017059623 discloses a novel class of alkynyl pyridine prolyl hydroxylase inhibitors. Among them, the compound shown in the formula (I) has a chemical name of 2- (3-hydroxy-5- (3-p-chlorophenoxypropyn-1-yl)) pyridine formylglycine, shows excellent proline hydroxylase inhibition effect, and is a potential new medicine for treating chronic anemia. The patent also discloses that the compound shown in the formula (I) can exist in the form of sodium salt, potassium salt and other pharmaceutically acceptable salts.
The compound exists in an episome form, and the bioavailability and the stability need to be further improved. In addition, the chemical stability of the medicine is often affected by the crystal form structure of the medicinal active ingredient, and the change of the crystal form structure of the compound may be caused by the difference of crystallization conditions and storage conditions, and sometimes other forms of crystal forms are generated. Generally, amorphous drug products do not have regular crystal structures and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor flowability and the like. Therefore, it is necessary to improve various properties of the above products, and intensive research is needed to find new crystal forms with high purity and good chemical stability.
Disclosure of Invention
The invention aims to provide a novel medicinal salt of a compound shown in a formula (I) and a crystal form thereof, and the novel salt and the crystal form have good stability and can be better applied to clinic.
The invention provides a I crystal form of a sodium salt of a compound shown as a formula (I), which is characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.636, 10.038, 19.165, 22.807, 25.169 and 27.050.
In a preferred embodiment, the present invention provides a crystalline form I of the sodium salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in figure 1.
The present invention further provides a process for preparing form I of the sodium salt of the compound of formula (I) comprising: dissolving free compound of formula (I) in any crystal form or amorphous form with sodium hydroxide or sodium salt of compound of formula (I) in any crystal form or amorphous form in appropriate amount of organic solvent (such as alcohol), preferably C), cooling, crystallizing, and filtering1～C6Alkyl alcohol, more preferably methanol.
In another aspect, the present invention provides a crystal form II of a sodium salt of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 4.811, 10.609, 12.428, 19.622, 20.934, 22.330, 23.388, 25.250 and 26.731.
In a preferred embodiment, the present invention provides a crystalline form II of the sodium salt of the compound of formula (I) characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 4.811, 10.609, 12.428, 17.760, 18.903, 19.622, 20.934, 22.330, 23.388, 24.361, 25.250, 26.731, 28.212, 29.185, 29.862, 31.555, 32.008 and 37.092.
In a preferred embodiment, the present invention provides a crystalline form II of the sodium salt of the compound of formula (I) characterized in that: the X-ray powder diffraction pattern is shown in figure 2.
The invention further provides a method for preparing the II crystal form of the sodium salt of the compound shown in the formula (I), which comprises the following steps: freeing the compound of formula (I) in any crystal form or amorphous formDissolving sodium hydroxide or sodium salt of compound of formula (I) in any crystal form or amorphous form in appropriate amount of organic solvent (such as alcohol), preferably C), cooling, crystallizing, and filtering1～C6Alkyl alcohol, more preferably one or two of ethanol and isopropanol.
In another aspect, the present invention provides a crystal form III of a sodium salt of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 9.492, 11.904, 14.355, 15.541, 16.846, 18.318, 18.866, 19.071, 19.670, 20.543, 22.562, 23.503 and 24.858.
In a preferred embodiment, the present invention provides a crystalline form III of the sodium salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 9.492, 11.904, 14.355, 15.541, 16.846, 18.318, 18.866, 19.071, 19.670, 20.543, 22.562, 23.503, 24.858, 25.384, 26.610, 27.216, 28.033, 28.962, 29.492, 31.118, 32.248, 33.822, 34.677, 39.616, 41.553 and 49.696.
In a preferred embodiment, the present invention provides a crystalline form III of the sodium salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in figure 3.
The invention further provides a process for preparing form III of the sodium salt of the compound of formula (I) comprising: dissolving free compound of formula (I) in any crystal form or amorphous form with sodium hydroxide or sodium salt of compound of formula (I) in any crystal form or amorphous form in proper amount of organic solvent, cooling, crystallizing, filtering, wherein the organic solvent can be selected from C1～C6Alkyl nitriles, preferably acetonitrile.
In another aspect, the present invention provides a crystal form IV of a sodium salt of a compound of formula (I), characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.633, 12.032, 12.896, 15.499, 16.507, 18.191, 18.461, 20.780, 23.370 and 26.024.
In a preferred embodiment, the present invention provides a crystalline form IV of the sodium salt of the compound of formula (I) characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.633, 12.032, 12.896, 15.499, 16.507, 18.191, 18.461, 20.780, 23.370, 24.208, 26.024, 26.655, 27.214, 27.890, 28.675, 29.746, 31.382, 35.175, 36.025, 37.797, 39.607, 39.917, 40.404, 42.504, 45.161 and 48.005.
In a preferred embodiment, the present invention provides a crystalline form IV of the sodium salt of the compound of formula (I) characterized in that: the X-ray powder diffraction pattern is shown in figure 4.
The present invention further provides a process for preparing form IV of the sodium salt of the compound of formula (I) comprising: dissolving the free compound shown in the formula (I) in any crystal form or amorphous state and sodium hydroxide or the sodium salt of the compound shown in the formula (I) in any crystal form or amorphous state in a proper amount of organic solvent by heating, cooling, crystallizing and filtering, wherein the organic solvent can be an ether solvent, and is preferably methyl tert-butyl ether.
In another aspect, the present invention provides a crystal form I of a potassium salt of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.955, 14.540, 16.117, 17.970, 20.927, 21.991, 23.687, 24.988 and 25.973.
In a preferred embodiment, the present invention provides a crystalline form I of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.955, 14.540, 16.117, 17.970, 20.927, 21.991, 23.687, 24.988, 25.973, 26.762, 27.629, 27.984, 28.536, 29.088, 29.601, 32.084, 34.253, 35.002, 36.303 and 38.550.
In a preferred embodiment, the present invention provides a crystalline form I of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 5.
The present invention further provides a process for preparing crystalline form I of the potassium salt of a compound of formula (I) comprising: mixing the free state of the compound shown in the formula (I) in any crystal form or amorphous form with potassium hydroxide or potassium salt of the compound shown in the formula (I) in any crystal form or amorphous formHeating to dissolve in appropriate amount of organic solvent, cooling, crystallizing, and filtering, wherein the organic solvent can be alcohol solvent, preferably C1～C6Alkyl alcohol, more preferably one or two of ethanol and isopropanol.
In another aspect, the present invention provides a crystal form II of a potassium salt of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.231, 8.065, 12.657, 13.614, 14.531, 16.226, 17.318 and 18.997.
In a preferred embodiment, the present invention provides a crystalline form II of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 7.231, 8.065, 12.657, 13.614, 14.531, 16.226, 17.318, 18.997, 21.805, 22.639, 24.858, 25.556, 25.896, 26.712, 27.570, 28.845, 29.603, 30.065, 31.078, 31.995, 32.992, 35.823 and 38.087.
In a preferred embodiment, the present invention provides a crystalline form II of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 6.
The invention further provides a process for preparing crystal form II of the potassium salt of a compound of formula (I), comprising: dissolving the free compound shown as the formula (I) in any crystal form or amorphous state and potassium hydroxide or potassium salt of the compound shown as the formula (I) in any crystal form or amorphous state in a proper amount of organic solvent by heating, cooling, crystallizing and filtering, wherein the organic solvent can be selected from C1～C6Alkyl nitriles, preferably acetonitrile.
In another aspect, the invention provides a crystal form III of a potassium salt of a compound of formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 5.295, 13.409, 16.150, 18.887, 20.664, 22.400, 24.214, 27.036 and 28.072.
In a preferred embodiment, the present invention provides a crystalline form III of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 5.295, 13.409, 16.150, 18.887, 20.664, 21.482, 22.400, 24.214, 25.037, 27.036, 28.072, 29.069, 29.698, 30.215, 31.041, 32.624, 33.388, 35.017, 35.818, 38.303, 41.164 and 43.982.
In a preferred embodiment, the present invention provides a crystalline form III of the potassium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 7.
The invention further provides a process for preparing crystal form III of the potassium salt of a compound of formula (I), comprising: dissolving the free compound shown in the formula (I) in any crystal form or amorphous state and potassium hydroxide or potassium salt of the compound shown in the formula (I) in any crystal form or amorphous state in a proper amount of organic solvent by heating, cooling, crystallizing and filtering, wherein the organic solvent can be an ether solvent, and methyl tert-butyl ether is preferred.
In another aspect of the invention, there is provided an ammonium salt of a compound of formula (I).
The present invention further provides a process for preparing an ammonium salt of a compound of formula (I) comprising: mixing the compound shown in the formula (I) with ammonium hydroxide.
In another aspect, the present invention provides a crystalline form I of an ammonium salt of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.582, 9.989, 13.381, 21.466, 22.722 and 23.640.
In a preferred embodiment, the present invention provides a crystalline form I of the ammonium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.582, 9.989, 13.381, 20.261, 21.466, 22.722, 23.640, 27.083 and 27.453.
In a preferred embodiment, the present invention provides a crystalline form I of the ammonium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.582, 9.989, 13.381, 15.205, 20.261, 21.466, 22.722, 23.640, 24.354, 24.926, 26.291, 27.083, 27.453, 29.443, 30.537, 31.233, 32.601, 34.068, 35.375, 35.938, 37.529 and 49.426.
In a preferred embodiment, the present invention provides a crystalline form I of the ammonium salt of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in figure 8.
The present invention further provides a process for preparing form I of the ammonium salt of the compound of formula (I) comprising: dissolving the free compound shown as the formula (I) in any crystal form or amorphous state and ammonium hydroxide or ammonium salt of the compound shown as the formula (I) in any crystal form or amorphous state in a proper amount of organic solvent by heating, cooling, crystallizing and filtering, wherein the organic solvent can be C1～C6Alkyl alcohol, C1～C6One or more of alkyl nitrile and ether solvent, preferably one or more of methanol, ethanol, isopropanol, acetonitrile and methyl tert-butyl ether.
In another aspect of the invention, there is provided a meglumine salt of a compound of formula (I).
The present invention further provides a process for the preparation of the meglumine salt of the compound of formula (I) comprising: mixing the compound shown in the formula (I) with meglumine.
In another aspect, the invention provides a crystal form I of meglumine salt of a compound represented by formula (I), which is characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.174, 9.432, 11.137, 12.655, 13.183, 15.621, 18.750, 20.021 and 20.849.
In a preferred embodiment, the present invention provides a crystalline form I of the meglumine salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.174, 9.432, 11.137, 12.655, 13.183, 15.621, 18.750, 20.021, 20.849, 21.997, 23.424, 24.115, 25.253 and 25.536.
In a preferred embodiment, the present invention provides a crystalline form I of the meglumine salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.174, 9.432, 11.137, 12.655, 13.183, 15.621, 18.750, 20.021, 20.849, 21.997, 23.424, 24.115, 25.253, 25.536, 26.483, 27.247, 28.465, 29.402, 29.947, 30.592, 32.009, 33.732, 34.395, 35.868, 36.648, 37.753, 38.195, 39.344, 42.348 and 44.248.
In a preferred embodiment, the present invention provides a crystalline form I of the meglumine salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 9.
The present invention further provides a process for preparing form I of the meglumine salt of the compound of formula (I) comprising: dissolving the free compound shown in the formula (I) in any crystal form or amorphous form and meglumine or the meglumine salt of the compound shown in the formula (I) in any crystal form or amorphous form in a proper amount of organic solvent by heating, cooling, crystallizing and filtering, wherein the organic solvent can be C1～C6Alkyl alcohol, C1～C6One or more of alkyl nitrile and ether solvent, preferably one or more of methanol, ethanol, isopropanol, acetonitrile and methyl tert-butyl ether.
The invention further relates to a pharmaceutical composition, which comprises one or more of crystal forms I, II, III and IV of sodium salt of a compound shown in formula (I), crystal forms I, II and III of potassium salt, crystal form I of ammonium salt and crystal form I of meglumine salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a pharmaceutical composition, which comprises one or more of ammonium salt and meglumine salt of the compound shown in the formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a pharmaceutical composition, which is prepared by mixing one or more of crystal forms I, II, III and IV of sodium salt of the compound shown in the formula (I), crystal forms I, II and III of potassium salt, crystal form I of ammonium salt and crystal form I of meglumine salt with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a pharmaceutical composition, which is prepared by mixing one or more of ammonium salt and meglumine salt of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a preparation method of a pharmaceutical composition containing the compound shown in the formula (I) or pharmaceutically acceptable salts thereof, which comprises the step of mixing one or more of crystal forms I, II, III and IV of sodium salt of the compound shown in the formula (I), crystal forms I, II and III of potassium salt, crystal form I of ammonium salt and crystal form I of meglumine salt with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a preparation method of a pharmaceutical composition containing the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, which comprises mixing one or more of ammonium salt and meglumine salt of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the crystalline form or pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
The invention further relates to the use of the crystal form I, II, III, IV of the sodium salt of the compound of formula (I), the crystal form I, II, III of the potassium salt, the crystal form I of the ammonium salt, the crystal form I of the meglumine salt or the pharmaceutical composition according to the invention for the preparation of a medicament for the treatment of a prolyl hydroxylase mediated disease, such as anemia, which can be treated by inhibiting prolyl hydroxylase.
The crystal form obtained by the invention is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystal form in the invention is conventional, such as volatile crystallization, cooling crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The 'pulping' of the invention refers to a method for purifying by utilizing the characteristic that a substance has poor solubility in a solvent but impurities have good solubility in the solvent, and the pulping purification can remove color, change crystal forms or remove a small amount of impurities.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The "X-ray powder diffraction pattern or XRPD" described herein is a pattern obtained by using Cu-ka radiation in an X-ray powder diffractometer.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The 2 theta or 2 theta angle refers to a diffraction angle, theta is a Bragg angle and has the unit of DEG or degree, and the error range of 2 theta is +/-0.3 or +/-0.2 or +/-0.1.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. Spatial lattice according to determined parallelepiped unitAnd (4) connecting and dividing to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
Advantageous effects of the invention
The crystal forms I, II, III and IV of the sodium salt of the compound shown in the formula (I), the crystal forms I, II and III of the sylvite, the ammonium salt, the meglumine salt and the crystal forms thereof have higher purity and good stability under the conditions of illumination, high temperature and high humidity; the HPLC purity has small change, high chemical stability and better solubility in a solvent compared with the existing free state, and is more favorable for the drug to play a role. The physical and chemical properties of the ammonium salt, the meglumine salt and the crystal form of the meglumine salt are more stable, and the sodium salt, the potassium salt and the crystal form of the meglumine salt are more favorable for clinic. The novel salt and crystal form of the compound shown in the formula (I) can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
FIG. 1 is an XRPD pattern for the crystal form I of the sodium salt of the compound of formula (I);
FIG. 2 is an XRPD pattern for form II of the sodium salt of the compound of formula (I);
FIG. 3 is an XRPD pattern for the form III crystal form of the sodium salt of the compound of formula (I);
FIG. 4 is an XRPD pattern for the IV crystal form of the sodium salt of the compound of formula (I);
FIG. 5 is an XRPD pattern for crystal form I of the potassium salt of the compound of formula (I);
FIG. 6 is an XRPD pattern for crystal form II of the potassium salt of the compound of formula (I);
FIG. 7 is an XRPD pattern for crystal form III of the potassium salt of the compound of formula (I);
FIG. 8 is an XRPD pattern for the ammonium salt of the compound of formula (I) in crystal form I;
FIG. 9 is an XRPD pattern for crystalline form I of the meglumine salt of the compound of formula (I);
FIG. 10 is a DSC of form I of the sodium salt of the compound of formula (I);
FIG. 11 is a DSC of form II of the sodium salt of the compound of formula (I);
FIG. 12 is a DSC chart of form III of the sodium salt of the compound of formula (I);
FIG. 13 is a DSC of form IV of the sodium salt of the compound of formula (I);
FIG. 14 is a DSC of crystal form I of the potassium salt of the compound of formula (I);
FIG. 15 is a DSC of crystal form II of the potassium salt of the compound of formula (I);
FIG. 16 is a DSC of crystal form III of the potassium salt of the compound of formula (I).
FIG. 17 is a DSC of form I of ammonium salt of compound of formula (I).
FIG. 18 is a DSC of form I of meglumine salt of the compound of formula (I).
FIG. 19 is an XRPD pattern for free form A of the compound of formula (I);
FIG. 20 is an XRPD pattern for the potassium salt amorphous form of the compound of formula (I)
FIG. 21 is an XRPD pattern comparing stability of free form A of the compound of formula (I);
FIG. 22 is an XRPD pattern comparing the stability of form I of the ammonium salt of the compound of formula (I);
figure 23 is an XRPD pattern comparing the form I stability of meglumine salt of the compound of formula (I).
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: MettlerToledo DSC 3+STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 25-300 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: bruker D8 Discover A25X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 4-60 degree
Voltage: 40KV, current: 40mA
Example 1
36mg of the compound of formula (I) (prepared according to the method disclosed in WO 2017059623) was weighed into a reaction flask, 1.2ml of methanol was added, 105. mu.l of 1mol/L sodium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the I crystal form of the sodium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 10, and the characteristic peak positions are shown in the following table:
TABLE 1 characteristic peaks of the sodium salt form I
Example 2
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of ethanol was added, 105. mu.l of 1mol/L sodium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 40 ℃ to obtain the II crystal form of the sodium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 2, the DSC pattern is shown in figure 11, and the characteristic peak positions are shown in the following table:
TABLE 2 characteristic peaks of the sodium salt II crystal form
Example 3
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of acetonitrile was added, 105. mu.l of 1mol/L sodium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the III crystal form of the sodium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 3, the DSC pattern is shown in figure 12, and the characteristic peak positions are shown in the following table:
TABLE 3 characteristic peaks of the sodium salt III crystal form
Example 4
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of methyl t-butyl ether was added, 105. mu.l of a 1mol/L sodium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the IV crystal form of the sodium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 4, the DSC pattern is shown in figure 13, and the characteristic peak positions are shown in the following table:
TABLE 4 characteristic peaks of sodium salt form IV
Example 5
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of ethanol was added, 105. mu.l of a 1mol/L potassium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the I crystal form of the potassium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 5, the DSC pattern is shown in figure 14, and the characteristic peak positions are shown in the following table:
TABLE 5 characteristic peaks of the potassium salt form I
Example 6
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of acetonitrile was added, 105. mu.l of a 1mol/L potassium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the II crystal form of the potassium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 6, the DSC pattern is shown in figure 15, and the characteristic peak positions are shown in the following table:
TABLE 6 characteristic peaks of crystal form of potassium salt II
Example 7
36mg of the compound represented by the formula (I) was weighed and charged into a reaction flask, 1.2ml of methyl t-butyl ether was added, 105. mu.l of a 1mol/L potassium hydroxide solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the III crystal form of the potassium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 7, the DSC pattern is shown in figure 16, and the characteristic peak positions are shown in the following table:
TABLE 7 characteristic peaks of potassium salt III crystal form
Example 8
180mg of the compound of the formula (I) is weighed and added into a reaction flask, 6ml of ethanol is added, 0.53ml of 1mol/L ammonium hydroxide solution is added while stirring at room temperature, and the mixture is stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the crystal form I of the ammonium salt of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 8, the DSC pattern is shown in figure 17, and the characteristic peak positions are shown in the following table:
TABLE 8 characteristic peaks of ammonium salt form I
Example 9
180mg of the compound represented by the formula (I) was weighed and put into a reaction flask, 6ml of ethanol was added, 0.53ml of 1mol/L aqueous N-methyl-D-glucamine solution was added under stirring at room temperature, and the mixture was stirred at room temperature for 30 min. Heating to 45 deg.C, and maintaining for 20 min; then cooling to 10 ℃, keeping for 2 hours, centrifuging and then drying in vacuum for 3 hours at 30 ℃ to obtain the I crystal form of the compound meglumine salt shown in the formula (I). The X-ray diffraction pattern is shown in figure 9, the DSC pattern is shown in figure 18, and the characteristic peak positions are shown in the following table:
TABLE 9 characteristic peaks of meglumine salt form I
Example 10
Physical stability tests are carried out on samples of the ammonium salt crystal form I and the meglumine salt crystal form I and free solids (determined as crystals and named as crystal form A) obtained according to the method of example 44 of WO2017059623 under different placing conditions, the test results are shown in Table 10, and XRPD patterns of stability determination of each crystal form are shown in figures 21-23.
TABLE 10 physical stability of the forms
Note: v represents that the crystal form is not changed; x represents the change of the crystal form; and/means not detected.
As can be seen from the table: the crystal form A is placed for 10 days under the condition of 0% humidity, the crystal form is transformed, and the crystal form is unstable. When the ammonium salt I crystal form is placed at 60 ℃, although the crystal form is not changed, the crystallinity is reduced to some extent; the meglumine salt crystal form I is not converted under various conditions, and the physical stability is better than that of ammonium salt.
Example 11
Samples of ammonium salt form I and meglumine salt form I of the compound of formula (I) were subjected to different conditions for chemical stability, and the results are shown in table 11. The purity of the crystal form is detected by HPLC, and a detection chromatographic column of ZORBAX SB-C18(4.6 x 1503.5 μm) and a mobile phase: TFA/MeOH/H2O, detection wavelength: 223 nm.
TABLE 11 chemical stability of the forms
As can be seen from table 11, the total impurity content of the ammonium salt form I under each condition was significantly increased; the impurity content of the meglumine salt crystal form I is not increased basically, and the stability of the meglumine salt crystal form I is better than that of the ammonium salt crystal form I.
Example 12
The solubility of the ammonium salt form I, the meglumine salt form I samples and the free form a in water was examined, and the results are shown in table 12.
TABLE 12 solubility in Water for each sample
| Crystal form | Ammonium salt crystal form I | Meglumine salt crystal form I | Crystal form A |
| Solubility (. mu.g/ml) | 1434.03 | 102050.06 | <200 |
As can be seen from the table, the solubility of meglumine salt form I in water is greatest.
Claims (7)
1. A crystalline form I of the meglumine salt of the compound of formula (I) characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 6.174, 9.432, 11.137, 12.655, 13.183, 15.621, 18.750, 20.021 and 20.849,
2. a crystalline form of a salt of a compound of formula (I) according to claim 1, characterized in that: the error range of the 2 theta angle is +/-0.2.
3. A pharmaceutical composition prepared by mixing the crystal form I of the meglumine salt of the compound of formula (I) as claimed in claim 1 with one or more pharmaceutically acceptable carriers, diluents or excipients.
4. A process for preparing the crystalline form I of the meglumine salt of the compound of formula (I) as claimed in claim 1, comprising: heating and dissolving the free compound shown in the formula (I) in any crystal form or amorphous form and meglumine or the meglumine salt of the compound shown in the formula (I) in any crystal form or amorphous form in a proper amount of organic solvent, cooling, crystallizing and filtering, wherein the organic solvent is selected from C1～C6Alkyl alcohol, C1～C6One or more of alkyl nitrile and ether solvent, wherein the ether solvent is methyl tert-butyl ether,
5. the production method according to claim 4, wherein the organic solvent is selected from one or more of methanol, ethanol, isopropanol, and acetonitrile.
6. Use of the crystalline form I of the meglumine salt of the compound of formula (I) according to claims 1-2 or the pharmaceutical composition according to claim 3 for the preparation of a medicament for the treatment of prolyl hydroxylase mediated diseases.
7. The use according to claim 6, wherein the disease is anemia.
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| CN111108098A (en) * | 2017-10-25 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | Crystal form of alkynyl pyridine prolyl hydroxylase inhibitor and preparation method thereof |
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| CN111108098A (en) * | 2017-10-25 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | Crystal form of alkynyl pyridine prolyl hydroxylase inhibitor and preparation method thereof |
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