CN115996720A - Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method thereof - Google Patents

Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method thereof Download PDF

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CN115996720A
CN115996720A CN202180052769.6A CN202180052769A CN115996720A CN 115996720 A CN115996720 A CN 115996720A CN 202180052769 A CN202180052769 A CN 202180052769A CN 115996720 A CN115996720 A CN 115996720A
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varactors
crystalline form
crystal
solvent
ray powder
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张娅璇
叶辉青
林碧悦
陈勇
黄芳芳
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Sunshine Lake Pharma Co Ltd
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of a hypoxia inducible factor prolyl hydroxylase inhibitor and a preparation method thereof. The X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks with 2 theta angles of 14.24, 18.16 and 20.12 degrees, or comprises diffraction peaks with 2 theta angles of 4.24, 16.80 and 33.99 degrees, or comprises diffraction peaks with 2 theta angles of 6.31, 21.12 and 24.18 degrees, or comprises diffraction peaks with 2 theta angles of 7.37, 15.58 and 20.92 degrees. Wherein, the crystal form has better performance and can be used for treating or preventing anemia; the preparation method of the crystal form is simple, convenient to operate and mild in condition.

Description

Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method thereof Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of a Hypoxia Inducible Factor (HIF) prolyl hydroxylase inhibitor and a preparation method thereof.
Background
Vardutaster (english name: vadadustat, CAS number: 1000025-07-9) chemical name { [5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl ] amino } acetic acid, developed by Akebia company, has the function of treating or preventing anemia, and has the mechanism of action of a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, which is in clinical three phases as an agent for treating anemia caused by secondary chronic kidney disease; the structural formula is shown in the figure:
Figure PCTCN2021116336-APPB-000001
The Akebia company discloses in WO2015073779A1 that vardutaster crystal form A, B, C, crystal form B can be converted into crystal form A in slurry at high temperature, wherein the crystal form A is a stable crystal form, but the solubility in water is very poor, the crystallinity of the crystal form B is poor, the stability is poor, the preparation condition of the crystal form C is severe, the preparation is difficult to prepare by a conventional method, and the reproducibility is poor. Patent WO2015073779A1 did not make any further screening studies on the crystalline form of valiroxostat.
Thus, there remains a need in the art for a systematic and comprehensive development of different crystalline forms of valiroxostat to find new crystalline forms and/or co-crystals that are more suitable for drug development.
Disclosure of Invention
Summary of The Invention
The invention provides a novel crystal form of vardost, a preparation method and a composition thereof.
In one aspect, the invention provides a crystalline form of varactors, known as the varactors-isonicotinal eutectic crystalline form. The X-ray powder diffraction pattern of the vardutaster-isonicotinal eutectic form comprises diffraction peaks at 14.24, 18.16 and 20.12 degrees 2 theta.
Thermogravimetric analysis curve shows that the crystal form has weight loss of 0.5% -10.0% at 100-200 ℃.
The differential scanning calorimetric curve of the crystal form has an endothermic peak at 150-210 ℃.
The invention also provides a method for preparing the vardos-isonicotin eutectic crystal form, which comprises the following steps: dissolving varactors in a solvent, adding isonicotin into the solution, stirring, filtering, and drying to constant weight to obtain varactors-isonicotin eutectic crystal forms.
In one aspect, the invention provides a crystalline form of varactors, referred to as a varactors-cinnamamide co-crystal form. The X-ray powder diffraction pattern of the varactors-cinnamamide co-crystal form comprises diffraction peaks at 2 theta angles of 4.24, 16.80 and 33.99 degrees.
Thermogravimetric analysis curve shows that the crystal form has weight loss of 0.01% -1.5% at 120-200 ℃.
The differential scanning calorimetric curve of the crystal form has an endothermic peak at 120-180 ℃.
The invention also provides a method for preparing the varactors-cinnamamide eutectic crystal form, which comprises the following steps: dissolving varactors in a solvent, adding cinnamamide into the solution, stirring, filtering, and drying to constant weight to obtain varactors-cinnamamide eutectic crystal forms.
In one aspect, the invention provides a crystalline form of varactors, referred to as a varactors-benzamide co-crystal form. The X-ray powder diffraction pattern of the varactors-benzamide co-crystal forms contained diffraction peaks at 6.31, 21.12 and 24.18 degrees 2 theta.
Thermogravimetric analysis curve shows that the crystal form has weight loss at 50-250 ℃ and the weight loss is 10.0-70.0%.
The differential scanning calorimetric curve of the crystal form has an endothermic peak at 90-150 ℃.
The invention also provides a method for preparing the varactors-benzamide eutectic crystal form, which comprises the following steps: dissolving varactors in good solvent, adding benzamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-benzamide eutectic crystal form.
In one aspect, the invention provides a crystalline form of varactors, referred to as a varactors-propionamide co-crystal form. The X-ray powder diffraction pattern of the crystalline form of the varactors-propionamide co-crystal form comprises diffraction peaks at 7.37, 15.58 and 20.92 degrees 2θ.
Thermogravimetric analysis curve shows that the crystal form has weight loss at 100-180 ℃ and the weight loss is 1.0-20.0%.
The differential scanning calorimetric curve of the crystal form has an endothermic peak at 80-150 ℃.
The invention also provides a method for preparing the varactors-propionamide eutectic crystal form, which comprises the following steps: dissolving varactors in good solvent, adding propionamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-propionamide eutectic crystal form.
In another aspect, the invention also provides a composition comprising any one or more of the foregoing crystalline forms of varactors. In some embodiments, the composition comprises at least 90% of the crystalline form of varactors by mass ratio. In some embodiments, the crystalline form does not exceed 0.5% -5% of pravastatin in the composition by mass ratio.
Definition of terms
The terms "comprising" or "including" are used in an open-ended fashion, i.e., including the teachings described herein, but not excluding additional aspects.
The term "crystalline form" is used to describe the state of existence of a solid compound and describes a collection of various parameters of ionic, atomic or molecular composition, symmetry properties and periodic arrangement within the crystal.
The term "relative intensity" refers to the ratio of the intensity of the first strong peak in a set of diffraction peaks belonging to a certain crystal form to the intensity of the first strong peak when the intensity of the first strong peak is defined as 100%.
The term "substantially as shown in the figures" means that at least 70%, at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.
In the context of the present invention, the values of 2theta (also known as 2theta or diffraction peak) in an X-ray powder diffraction pattern are all in degrees (°).
When referring to a spectrum and/or data in a graph, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.
The X-ray powder diffraction peaks of the crystalline form, the measurement of which has experimental errors in the 2θ or diffraction peaks of the X-ray powder diffraction pattern, may differ slightly between one machine and another and between one sample and another, the values of which may be +/-0.2 units or +/-0.1 units or +/-0.05 units, and thus the values of which cannot be considered absolute.
The differential scanning calorimetric curve (DSC) of the crystalline form has experimental errors, and the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the experimental error or difference may have a value of 5 ℃ or less, or 4 ℃ or less, or 3 ℃ or less, or 2 ℃ or less, or 1 ℃ or less, so the peak position or peak value of the endothermic peak of the DSC cannot be regarded as absolute.
Thermal Gravimetric Analysis (TGA) of the crystalline form has experimental errors, and the weight loss temperature and the weight loss may vary slightly from one machine to another and from one sample to another, and the experimental errors or differences may be about +/-0.1 units, about +/-0.05 units, or about +/-0.01 units, so the weight loss temperature and weight loss values cannot be considered absolute.
In the context of the present invention, whether or not the words "about" or "about" are used, all numbers disclosed herein are approximations, each number may vary by +1%,.+ -. 2%, or.+ -. 5%.
"room temperature" means a temperature of about 15 ℃ to 32 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 28 ℃.
In the present invention, the solid is dried to a constant weight when the solid is dried.
Detailed Description
The inventor develops a crystal form of the compound valdostart and a preparation method thereof through research.
The varactors provided by the invention are called varactors-isonicotins eutectic crystal forms, varactors-cinnamamides eutectic crystal forms, varactors-benzamide eutectic crystal forms and varactors-propionamides eutectic crystal forms, and the varactors-propionamides eutectic crystal forms have good performance, high solubility and high bioavailability; or/and has good stability, is favorable for storage, and meets the requirement of drug stability; low hygroscopicity, or/and good performance in electrostatic property, low electrostatic property, and is beneficial to operation in production process.
In a first aspect, the present invention provides a novel crystalline form of varactors, known as the varactors-isonicotinal eutectic crystalline form.
The vardostat-isonicotin eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern comprises diffraction peaks with 2 theta angles of 14.24, 18.16 and 20.12 degrees.
In some embodiments, the vardos-isonicotin co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 7.68, 14.24, 15.27, 18.16, 20.12 and 30.43 degrees 2 theta.
In some embodiments, the vardos-isonicotin co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 7.68, 10.86, 14.24, 15.27, 18.16, 20.12, 25.84, 29.18, 29.52, 30.43, 31.23, 36.85 and 39.32 degrees 2θ.
In some embodiments, the vardos-isonicotin co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 7.68, 10.86, 25.84, 29.18 and 30.43 degrees 2θ.
In some embodiments, the vardos-isonicotin co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 14.24, 15.27, 29.52, 31.23 and 36.85 degrees 2θ.
In some embodiments, the vardos-isonicotin co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 18.16, 20.12, 25.84, 36.85 and 39.32 degrees 2 theta.
In some embodiments, the crystalline form of vardutaster-isonicotin co-crystals has an X-ray powder diffraction pattern comprising at least one, or at least two, or three, of the diffraction peaks at 2θ angles of 14.24, 18.16, and 20.12 degrees.
In some embodiments, the X-ray powder diffraction pattern of the varactors-isonicotinal co-crystal form is substantially as shown in figure 1.
The varactors-isonicotin eutectic crystal form is the eutectic of varactors and isonicotin. In some embodiments, the molar ratio of vardutaster to isonicotin is 1:1.
The vardostat-isonicotin eutectic crystal form also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of 0.5% -10.0% at 100 ℃ -200 ℃. In some embodiments, thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 2.1% at 100 ℃ to 200 ℃. In a specific embodiment, the thermogravimetric analysis graph (TGA) is substantially as shown in figure 2.
The vardostat-isonicotin eutectic crystal form also has the following characteristics: the differential scanning calorimetric curve (DSC) of the crystalline form has an endothermic peak at 150 ℃ to 210 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 160 ℃ -200 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 170 ℃ -190 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm peak at 176 ℃ -180 ℃ with an endotherm peak top value of 178 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the vardutaster-isonicotin eutectic crystalline form is substantially as shown in figure 2.
In a second aspect, the invention provides two methods for preparing the vardutaster-isonicotin eutectic crystal form.
The preparation method of the varactors-isonicotin eutectic crystal form is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.
A process for preparing the varactors-isonicotinal eutectic crystal form comprising: dissolving varactors in a solvent, adding isonicotin into the solution, stirring, filtering, and drying to constant weight to obtain varactors-isonicotin eutectic crystal forms.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent is acetone.
In some embodiments, the concentration of the varactors-isonicotinal eutectic crystal form is 5mg/ml to 300mg/ml after the varactors are completely dissolved in the solvent during the preparation process. In some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 200mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 100mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 50mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 200mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 100mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 50mg/ml; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in the solvent.
Another method of preparing the varactors-isonicotins eutectic crystal form, comprising: dissolving vardost in a good solvent, adding isonicotin into the solution, adding the poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain the vardost-isonicotin eutectic crystal form.
In some embodiments, the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether. In some embodiments, the poor solvent comprises DMF and the poor solvent comprises water. In some embodiments, the good solvent is DMF and the poor solvent is water.
In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3. In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:3.
In some embodiments, the concentration of the varactors-isonicotinal eutectic crystal form is 5mg/ml-300mg/ml after the varactors are completely dissolved in the good solvent during the preparation process. In some embodiments, when the pravastatin is fully dissolved in the good solvent, the concentration is from 5mg/ml to 200mg/ml; in some embodiments, the concentration of pravastatin is from 5mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 5mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 200mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in good solvent.
In a third aspect, the present invention provides a novel crystalline form of varactors, known as the varactors-cinnamamide co-crystalline form.
The vardutasteride-cinnamamide eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern comprises diffraction peaks with 2 theta angles of 4.24, 16.80 and 33.99 degrees.
In some embodiments, the varactors-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2θ angles of 4.24, 12.58, 16.80, 21.04, 29.62 and 33.99 degrees.
In some embodiments, the varactors-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 4.24,8.38, 12.58, 14.14, 16.80, 20.18, 21.04, 25.32, 29.62, 33.99, 38.39 and 39.13 degrees 2θ.
In some embodiments, the varactors-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 4.24,8.38, 20.18, 25.32, 33.99 and 38.39 degrees 2 theta.
In some embodiments, the varactors-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2θ angles of 12.58, 14.14, 16.80, 20.18, 25.32 and 39.13 degrees.
In some embodiments, the varactors-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 8.38, 14.14, 21.04, 25.32, 29.62 and 38.39 degrees 2 theta.
In some embodiments, the crystalline form of varactors-cinnamamide has an X-ray powder diffraction pattern comprising at least one, or at least two, or three, of the diffraction peaks having 2θ angles of 4.24, 16.80, and 33.99 degrees.
In some embodiments, the X-ray powder diffraction pattern of the varactors-cinnamamide co-crystal form is substantially as shown in figure 3.
The varactors-cinnamamide eutectic crystal form is the eutectic of varactors and cinnamamide. In some embodiments, the molar ratio of varactors to cinnamamide is 1:1.
The vardutasteride-cinnamamide eutectic crystal form also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of 0.01% -1.5% at 120 ℃ -200 ℃. In some embodiments, the thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 0.18% at 120 ℃ to 200 ℃. In a specific embodiment, the thermogravimetric analysis graph (TGA) is substantially as shown in figure 4.
The vardutasteride-cinnamamide eutectic crystal form also has the following characteristics: the differential scanning calorimetric curve (DSC) of the crystalline form has an endothermic peak at 120-180 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 140 ℃ -160 ℃. In some embodiments, the differential scan of the crystalline form has an endothermic peak at 150 ℃ to 154 ℃ with an endothermic peak top value of 152 ℃. In a specific embodiment, the varactors-cinnamamide co-crystal form has a Differential Scanning Calorimetry (DSC) substantially as shown in figure 4.
In a fourth aspect, the invention provides two preparation methods of the varactors-cinnamamide eutectic crystal form.
The preparation method of the varactors-cinnamamide eutectic crystal form is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.
A process for preparing the varactors-cinnamamide co-crystal form comprising: dissolving varactors in a solvent, adding cinnamamide into the solution, stirring, filtering, and drying to constant weight to obtain varactors-cinnamamide eutectic crystal forms.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile. In some embodiments, the solvent comprises ethyl acetate. In some embodiments, the solvent is ethyl acetate.
In some embodiments, the concentration of the varactors-cinnamamide co-crystal form is between 5mg/ml and 300mg/ml after the varactors are completely dissolved in the solvent during the preparation process. In some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 200mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 100mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 5mg/ml to 50mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 200mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 100mg/ml; in some embodiments, when the varactors are completely dissolved in the solvent, the concentration is 10mg/ml to 50mg/ml; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in the solvent.
Another method for preparing the varactors-cinnamamide eutectic crystal form comprises: dissolving varactors in good solvent, adding cinnamamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-cinnamamide eutectic crystal form.
In some embodiments, the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether. In some embodiments, the poor solvent comprises DMF and the poor solvent comprises water. In some embodiments, the good solvent is DMF and the poor solvent is water.
In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3. In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:3.
In some embodiments, the concentration of the varactors-cinnamamide co-crystal form is 5mg/ml to 300mg/ml after the varactors are completely dissolved in the good solvent during the preparation process. In some embodiments, when the pravastatin is fully dissolved in the good solvent, the concentration is from 5mg/ml to 200mg/ml; in some embodiments, the concentration of pravastatin is from 5mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 5mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 200mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in good solvent.
In a fifth aspect, the present invention provides a novel crystalline form of varactors, known as the varactors-benzamide co-crystal form.
The vardutaster-benzamide eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern comprises diffraction peaks with 2 theta angles of 6.31, 21.12 and 24.18 degrees.
In some embodiments, the varactors-benzamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 6.31, 15.58, 17.59, 21.12, 24.18 and 25.05 degrees 2 theta.
In some embodiments, the varactors-benzamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2θ angles 6.31,9.22, 10.41, 13.50, 14.98, 15.58, 17.59, 18.24, 18.99, 20.93, 21.12, 24.18, 25.05, 27.42, 27.91, 28.06, 33.63 and 36.51 degrees.
In some embodiments, the varactors-benzamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 6.31,9.22, 10.41, 25.05, 27.42 and 33.63 degrees 2θ.
In some embodiments, the varactors-benzamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 13.50, 15.58, 18.24, 20.93, 24.18 and 36.51 degrees 2 theta.
In some embodiments, the varactors-benzamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2θ angles of 14.98, 17.59, 18.99, 21.12, 27.91 and 28.06 degrees.
In some embodiments, the crystalline form of varactors-benzamide co-crystals has an X-ray powder diffraction pattern comprising at least one, or at least two, or three of the diffraction peaks at 2θ angles of 6.31, 21.12, and 24.18 degrees.
In some embodiments, the X-ray powder diffraction pattern of the co-crystal form of varactors-benzamide is substantially as shown in figure 5.
The varactors-benzamide eutectic crystal form is the eutectic of varactors and benzamide. In some embodiments, the molar ratio of varactors to benzamide is 1:2.
The vardutaster-benzamide eutectic crystal form also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of 10.0% -70.0% at 50 ℃ -250 ℃. In some embodiments, thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 45.3% at 50 ℃ to 250 ℃. In a specific embodiment, the thermogravimetric analysis graph (TGA) is substantially as shown in figure 6.
The vardutaster-benzamide eutectic crystal form also has the following characteristics: the differential scanning calorimetric curve (DSC) of the crystalline form has an endothermic peak at 90 ℃ to 150 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 100 ℃ -140 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 110 ℃ -130 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 117 ℃ -121 ℃ with an endotherm peak top value of 119 ℃. In a specific embodiment, the varactors-benzamide eutectic crystal form has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 6.
In a sixth aspect, the invention provides a method for preparing the varactors-benzamide eutectic crystal form.
The preparation method of the varactors-benzamide eutectic crystal form is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.
A process for preparing the co-crystal form of varactors-benzamide comprising: dissolving varactors in good solvent, adding benzamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-benzamide eutectic crystal form.
In some embodiments, the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether. In some embodiments, the poor solvent comprises acetone and the poor solvent comprises n-heptane. In some embodiments, the good solvent is acetone and the poor solvent is n-heptane.
In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:4. In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:3; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:4.
In some embodiments, the concentration of the varactors-benzamide co-crystal form is between 5mg/ml and 300mg/ml after the varactors are completely dissolved in the good solvent during the preparation process. In some embodiments, when the pravastatin is fully dissolved in the good solvent, the concentration is from 5mg/ml to 200mg/ml; in some embodiments, the concentration of pravastatin is from 5mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 5mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 200mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in good solvent.
In a seventh aspect, the present invention provides a novel crystalline form of varactors, known as the varactors-propionamide co-crystal form.
The vardutaster-propionamide eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern comprises diffraction peaks at 7.37, 15.58 and 20.92 degrees 2 theta.
In some embodiments, the varactors-propionamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 7.37,9.11, 15.58, 17.18, 20.92 and 31.08 degrees 2 theta.
In some embodiments, the varactors-propionamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2θ angles 7.37,9.11, 11.09, 13.66, 13.93, 14.82, 15.58, 17.18, 18.11, 20.42, 20.92, 21.69, 22.37, 23.99, 24.78, 28.12, 28.34 and 31.08 degrees.
In some embodiments, the varactors-propionamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 7.37, 13.93, 14.82, 21.69, 28.34 and 31.08 degrees 2 theta.
In some embodiments, the varactors-propionamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 9.11, 11.09, 13.66, 20.92, 22.37 and 24.78 degrees 2 theta.
In some embodiments, the varactors-propionamide co-crystal forms have the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 15.58, 17.18, 18.11, 20.42, 23.99 and 28.12 degrees 2 theta.
In some embodiments, the crystalline form of varactors-propionamide has an X-ray powder diffraction pattern comprising at least one, or at least two, or three, of the diffraction peaks at 2θ angles of 7.37, 15.58, and 20.92 degrees.
In some embodiments, the X-ray powder diffraction pattern of the co-crystal form of varactors-propionamide is substantially as shown in fig. 7.
The varactors-propionamide eutectic crystal form is the eutectic of varactors and propionamide. In some embodiments, the molar ratio of varactors to propionamide is 1:2.
The vardutaster-propionamide eutectic crystal form also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of 1.0% -20.0% at 100 ℃ -180 ℃. In some embodiments, thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 12.1% at 100 ℃ to 180 ℃. In a specific embodiment, the thermogravimetric analysis graph (TGA) is substantially as shown in figure 8.
The vardutaster-propionamide eutectic crystal form also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 80-150 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 100 ℃ -130 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm at 110 ℃ -120 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endotherm peak at 112 ℃ -116 ℃ with an endotherm peak top value of 114 ℃. In a specific embodiment, the varactors-propionamide eutectic crystal form has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 8.
In an eighth aspect, the invention provides a method for preparing the varactors-propionamide eutectic crystal form.
The preparation method of the varactors-propionamide eutectic crystal form is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.
A process for preparing the varactors-propionamide eutectic crystal form comprising: dissolving varactors in good solvent, adding propionamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-propionamide eutectic crystal form.
In some embodiments, the good solvent comprises at least one selected from the group consisting of ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether. In some embodiments, the poor solvent comprises ethyl acetate and the poor solvent comprises n-heptane. In some embodiments, the good solvent is ethyl acetate and the poor solvent is n-heptane.
In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3. In some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:3.
In some embodiments, the concentration of the varactors-propionamide co-crystal forms is between 5mg/ml and 300mg/ml after the varactors are completely dissolved in the good solvent during the preparation process. In some embodiments, when the pravastatin is fully dissolved in the good solvent, the concentration is from 5mg/ml to 200mg/ml; in some embodiments, the concentration of pravastatin is from 5mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 5mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 200mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 100mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration of pravastatin is from 10mg/ml to 50mg/ml after complete dissolution in the good solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after complete dissolution of varactors in good solvent.
In a ninth aspect, the invention also provides a composition comprising any of the foregoing crystalline forms of vallisat.
In the composition, the crystal form or salt is at least 90% of valiroxostat or the crystal form is not more than 0.5% -5% of valiroxostat according to the weight ratio.
In some embodiments, the composition comprises: at least one of the foregoing crystalline forms, and a pharmaceutically acceptable adjuvant or carrier; wherein, according to the weight ratio, the crystal form or salt is at least 90% of the valiroxostat, or the crystal form is not more than 0.5% -5% of the valiroxostat.
In some embodiments, a composition comprises the foregoing crystalline form of valdriver, wherein the crystalline form is at least 90% of valdriver. In some embodiments, a composition comprises the foregoing crystalline form of valiroxostat, wherein the crystalline form is at least 95%, or at least 99% of valiroxostat, by weight. In some embodiments, a composition comprises the foregoing crystalline form of valdriver, wherein the crystalline form is at least 0.5% -5% of valdriver. In some embodiments, a composition comprises the foregoing crystalline form of valdriver, wherein the crystalline form is at least 5% of valdriver. In some embodiments, a composition comprises the foregoing crystalline form of valdriver, wherein the crystalline form does not exceed 0.5% -5% of valdriver. In some embodiments, a composition comprises the foregoing crystalline form of valdriver, wherein the crystalline form does not exceed 5% of valdriver.
In some embodiments, a composition comprises the foregoing crystalline form of varactors, which is at least one of a varactors-isonicotinal crystalline form, a varactors-cinnamamide eutectic crystalline form, a varactors-benzamide eutectic crystalline form, a valactors-propionamide eutectic crystalline form. In some embodiments, a composition comprises the foregoing crystalline form of varactors-isonicotins, crystalline form of varactors-cinnamamides, crystalline form of varactors-benzamides, crystalline form of varactors-propionamides.
In some embodiments, a composition comprises at least one of the foregoing varactors-isonicotins co-crystal forms, varactors-cinnamamides co-crystal forms, varactors-benzamide co-crystal forms, valactors-propionamides co-crystal forms, and combinations thereof; wherein, the crystal form is at least 90% of the varactors calculated by the varactors. In some embodiments, a composition comprises the foregoing varactors-isonicotinal crystalline form, varactors-cinnamamide eutectic crystalline form, varactors-benzamide eutectic crystalline form, varactors-propionamide eutectic crystalline form, wherein the crystalline form is at least 90% of varactors. In some embodiments, a composition comprises the foregoing varactors-isonicotinal crystalline form, varactors-cinnamamide eutectic crystalline form, varactors-benzamide eutectic crystalline form, varactors-propionamide eutectic crystalline form, wherein the crystalline form is at least 95%, or at least 99% of varactors.
In some embodiments, a composition comprises at least one of the foregoing varactors-isonicotins co-crystal forms, varactors-cinnamamides co-crystal forms, varactors-benzamide co-crystal forms, valactors-propionamides co-crystal forms, and combinations thereof; wherein, the crystal form is at least 0.5% -5% of the varactors calculated by the varactors. In some embodiments, a composition comprises the foregoing varactors-isonicotinal crystalline form, varactors-cinnamamide eutectic crystalline form, varactors-benzamide eutectic crystalline form, varactors-propionamide eutectic crystalline form, wherein the crystalline form is at least 0.5% -5% varactors. In some embodiments, a composition comprises the foregoing varactors-isonicotinal crystalline form, varactors-cinnamamide eutectic crystalline form, varactors-benzamide eutectic crystalline form, varactors-propionamide eutectic crystalline form, wherein the crystalline form is at least 5% of varactors. In some embodiments, a composition comprises the foregoing varactors-isonicotinal crystalline form, varactors-cinnamamide eutectic crystalline form, varactors-benzamide eutectic crystalline form, varactors-propionamide eutectic crystalline form, wherein the crystalline form is no more than 0.5% -5% of varactors. In some embodiments, a composition comprises the foregoing crystalline form of varactors-isonicotins, crystalline form of varactors-cinnamamides, crystalline form of varactors-benzamides and/or crystalline form of varactors-propionamides, wherein the crystalline form is no more than 5% of varactors.
The composition can also comprise pharmaceutically acceptable auxiliary materials or carriers. The pharmaceutically acceptable auxiliary materials or carriers can comprise filling agents, diluents, lubricants and the like. In some embodiments, the composition further comprises a pharmaceutically acceptable adjuvant or carrier comprising a lubricant. In some embodiments, the lubricant is magnesium stearate.
The composition can be prepared into any suitable pharmaceutical preparation, such as tablets, capsules, granules, suspensions, injection and the like.
Drawings
FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of the crystalline form of vardost-isonicotin co-crystals;
FIG. 2 shows a differential scanning calorimeter profile (DSC) and thermogravimetric analysis profile (TGA) of a crystalline form of vardutaster-isonicotinal eutectic;
FIG. 3 shows an X-ray powder diffraction pattern (XRPD) of the co-crystalline form of varactors-cinnamamide;
FIG. 4 shows a differential scanning calorimeter profile (DSC) and thermogravimetric analysis profile (TGA) of a crystalline form of varactors-cinnamamide co-crystal;
FIG. 5 shows an X-ray powder diffraction pattern (XRPD) of the co-crystalline form of varactors-benzamide;
FIG. 6 shows a differential scanning calorimeter profile (DSC) and thermogravimetric analysis profile (TGA) of a crystalline form of varactors-benzamide co-crystal;
FIG. 7 shows an X-ray powder diffraction pattern (XRPD) of the co-crystalline form of varactors-propionamide;
FIG. 8 shows a differential scanning calorimeter profile (DSC) and thermogravimetric analysis profile (TGA) of a crystalline form of varactors-propionamide co-crystal;
FIG. 9 shows X-ray powder diffraction patterns (XRPD) of the crystalline form of vardost-isonicotin after being placed under high temperature, high humidity and light conditions for 15 days (0 days, high humidity 15 days, high temperature 15 days and light 15 days in order from bottom to top);
FIG. 10 shows X-ray powder diffraction patterns (XRPD) of the varactors-cinnamamide eutectic crystal form after being placed under high temperature, high humidity and light conditions for 15 days (0 days, high humidity 15 days, high temperature 15 days and light 15 days in order from bottom to top);
FIG. 11 shows X-ray powder diffraction patterns (XRPD) of the varactors-benzamide eutectic crystal form after and before 15 days of standing under high temperature, high humidity and light conditions (0 days, high humidity 15 days, high temperature 15 days and light 15 days in order from bottom to top);
FIG. 12 shows X-ray powder diffraction patterns (XRPD) of the varactors-propionamide co-crystal forms after and before 15 days of standing under high temperature, high humidity, and light conditions (0 days, high humidity 15 days, high temperature 15 days, and light 15 days in order from bottom to top);
FIG. 13 shows X-ray powder diffraction patterns (XRPD) of the crystalline form of varactors-isonicotins after 12 months of standing under long term stability conditions (0 days in order from bottom to top, long term 12 months);
Fig. 14 shows the X-ray powder diffraction pattern (XRPD) of the crystalline form of varactors-benzamide co-crystals after 12 months of standing under long term stability conditions (0 days in order from bottom to top, long term 12 months).
Detailed Description
In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.
The reagents used in the present invention are all commercially available or can be prepared by methods of the prior art or by methods described in the present invention.
In the invention, DEG C represents DEG C, mg represents milligrams, mL represents milliliters, h represents hours, min represents minutes, DMF is N, N-dimethylformamide, and DMSO is dimethyl sulfoxide.
Instrument parameters
All analyses below were performed at room temperature unless otherwise specified in the parameters.
X-ray powder diffraction (XRPD)
X-ray powder diffraction (XRPD) patterns were collected on a netherlands PANalytical Empyrean X-ray diffractometer equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source is (Cu, kα, kα1)
Figure PCTCN2021116336-APPB-000002
1.540598；Kα2
Figure PCTCN2021116336-APPB-000003
1.544426; kα2/kα1 intensity ratio: 0.50 With a voltage set at 45KV and a current set at 40 mA.X-ray beam divergence, i.e. X on the sample The effective size of the ray constraint is 10mm, and an effective 2 theta range of 3-60 degrees is obtained by adopting a theta-theta continuous scanning mode. And taking a proper amount of sample, lightly pressing the sample at the circular groove of the zero background sample frame under the environmental condition (about 18-32 ℃), obtaining a flat plane by using a clean glass slide, and fixing the zero background sample frame. The sample was scanned in a step size of 0.0167 ° to produce a conventional XRPD pattern in the range of 3-60 ° 2θ±0.2°. The software used for Data collection was Data color, and Data was analyzed and presented with Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate represents the diffraction intensity expressed in terms of a number (counts), and the abscissa represents the diffraction angle 2θ expressed in terms of degrees (°).
Differential Scanning Calorimetry (DSC)
Using TA Instruments TM In model Q2000, a sealing disk device was used. Samples (about 1-3 mg) were weighed in aluminum pans, capped with Tzero, recorded precisely to one hundred milligrams, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected at a heating rate of 10 ℃/min between room temperature and 300 ℃. The plot was drawn with the endothermic peak down and the data was analyzed and displayed with TA Universal Analysis. In the DSC chart, the abscissa indicates Temperature (DEG C), and the ordinate indicates Heat Flow (Heat Flow, W/g) emitted per unit mass of the substance.
Thermogravimetric analysis (TGA)
TGA measurements at TA Instruments TM Model Q500. The operation steps are that the empty crucible is peeled, the solid sample is taken to be about 10mg, and the solid sample is evenly paved in the peeled empty crucible. After the instrument is stable in operation, data are collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ under nitrogen purging, and a map is recorded. In the TGA graph, the abscissa represents Temperature (DEG C) and the ordinate represents Weight percent (Weight).
Preparation of vardutaster-isonicotin eutectic crystal form
Example 1
150mg of crude vardutaster (not limited to solid form) is added into 5ml of acetone solvent, after stirring at room temperature to obtain a clear solution, 61.06mg of isonicotinic acid is slowly added, stirring is carried out for one day, white solid is separated out, suction filtration is carried out, and the obtained product is placed in a drying box at 50 ℃ for vacuum drying for 24 hours, so that about 140mg of white solid is obtained. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 1 and 2.
Example 2
150mg of crude vardutaster (not limited to solid form) is added into 1ml of DMF solvent, after stirring at room temperature to obtain a clear solution, 121mg of isonicotinic acid is slowly added, stirring at room temperature is carried out without precipitating solid, then 2ml of water is added, stirring is carried out overnight to precipitate white solid, suction filtration is carried out, and the obtained solution is placed in a drying box at 50 ℃ for vacuum drying for 24 hours, so that about 130mg of white solid is obtained. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 1 and 2.
Preparation of vardutaster-cinnamamide eutectic crystal form
Example 3
150mg of crude vardutaster (not limited to solid form) is added into 5ml of ethyl acetate solvent, heated to 50 ℃ and stirred to obtain clear solution, 73.58mg of cinnamamide is slowly added, cooled to room temperature and stirred for one day, white solid is separated out, filtered by suction and placed in a drying box at 50 ℃ for vacuum drying for 24 hours, and about 130mg of white solid is obtained. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 3 and 4.
Example 4
150mg of crude vardutaster (not limited to solid form) is added into 1ml of DMF solvent, stirred at room temperature to obtain clear solution, 73.58mg of cinnamamide is slowly added, stirred at room temperature to precipitate no solid, then 2ml of water is added, stirred overnight to precipitate white solid, suction filtration is carried out, and the obtained solution is placed in a drying box at 50 ℃ for vacuum drying for 24 hours to obtain about 130mg of white solid. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 3 and 4.
Preparation of vardutaster-benzamide eutectic crystal form
Example 5
150mg of crude vardutaster (not limited to solid form) is added into 2ml of acetone solvent, after stirring at room temperature to obtain a clear solution, 121mg of benzamide is slowly added, stirring at room temperature is carried out, no solid is precipitated, then 6ml of n-heptane is added, stirring is carried out overnight, white solid is precipitated, suction filtration is carried out, and the mixture is placed in a drying oven at 50 ℃ for vacuum drying for 24 hours, thus obtaining about 150mg of white solid. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 5 and 6.
Preparation of vardutaster-propionamide eutectic crystal form
Example 6
150mg of crude vardutaster (not limited to solid form) is added into 2ml of ethyl acetate solvent, heated to 50 ℃ and stirred for dissolving, 73.09mg of propionamide is slowly added, stirring is carried out at room temperature, no solid is precipitated, then 4ml of n-heptane is added, stirring is carried out overnight, white solid is precipitated, suction filtration is carried out, and the obtained mixture is placed in a drying oven at 50 ℃ for vacuum drying for 24 hours, thus obtaining about 100mg of white solid. The X-ray powder diffraction pattern, DSC and TGA patterns thereof were measured as shown in fig. 7 and 8.
Example 7 solubility test
According to the solubility test guidelines of the current Chinese pharmacopoeia, experiments were designed to measure the solubility of the crystalline form of varactors in water and buffer with a pH of 6.8, respectively, the solubility values were calculated as varactors, and the results are shown in tables 1 and 2. The results show that the solubility of the varactors-isonicotinal eutectic and the varactors-benzamide eutectic in water and buffer with the pH of 6.8 is significantly higher than that of the varactors-crystalline form A, wherein the solubility of the varactors-isonicotinal eutectic in water is 1.6 times that of the varactors-crystalline form A, and the solubility of the varactors-benzamide eutectic in water is 1.18 times that of the varactors-crystalline form A; the solubility of the varactors-isonicotin eutectic in the buffer with the pH value of 6.8 is 1.2 times that of the varactors-benzamide eutectic in the buffer with the pH value of 6.8, and the solubility of the varactors-isonicotin eutectic in the buffer with the pH value of 6.8 is 1.8 times that of the varactors-crystalline form A; the solubility of the varactors-cinnamamide eutectic in the buffer with pH of 6.8 is also higher, which is 1.8 times that of varactors form A.
Table 1: solubility in water data (37 ℃ C., water)
Sample of Solubility (in terms of vardutaster, mg/ml)
Vardutaster crystal form A 0.0271
Vardutaster-isonicotin co-crystal 0.0439
Vardostat-benzamide co-crystals 0.032
Table 2: solubility data in buffer (37 ℃, ph=6.8 phosphate buffer)
Sample of Solubility (in terms of vardutaster, mg/ml)
Vardutaster crystal form A 1.0457
Vardutaster-isonicotin co-crystal 1.252
Vardutaster-cinnamamide eutectic 1.9224
Vardostat-benzamide co-crystals 1.9172
Vardutaster-propionamide eutectic 1.0296
Example 8 stability investigation
According to the guiding principle of the pharmaceutical preparation stability test, the influence factor experiment, including the high temperature test, the high humidity test and the strong light irradiation test, is carried out on the valirst crystal form, and the stability condition affecting the crystal form is examined, and the results are shown in table 3.
High temperature test: and respectively taking a proper amount of crystal form samples, spreading the crystal form samples in a weighing bottle, placing the crystal form samples in a constant temperature and humidity box with the RH of 75+/-5% at 60+/-5 ℃, and then taking about 100mg of the crystal form samples in 0, 5 and 15 days respectively, and testing the crystal form conditions by adopting powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
High humidity test: and respectively taking a proper amount of crystal form samples, spreading the crystal form samples in a weighing bottle, placing the crystal form samples in a constant temperature and humidity box with RH of 92.5+/-5 percent at 25 ℃, then taking about 100mg of the crystal form samples respectively at 0, 5 and 15 days, and testing the crystal form conditions by adopting powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
Illumination test: and respectively taking a proper amount of crystal form samples, spreading the samples into a weighing bottle, placing the samples under the conditions of a constant temperature and humidity box (25 ℃ and RH 60% +/-5%) with visible light of 4500 Lux+/-500 Lux (VIS) and ultraviolet light of 1.7W/m < 2 > (UV), and then taking about 100mg of the samples respectively in 0 days, 5 days and 15 days, and testing the crystal form by adopting powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
Table 3: stability data of 4 eutectic crystal forms of valdost under influence factor conditions
Figure PCTCN2021116336-APPB-000004
The results show that after the vardos-isonicotin eutectic crystal form, the vardos-cinnamamide eutectic crystal form and the valdos-benzamide eutectic crystal form are placed for 15 days under the test conditions of three influencing factors of high temperature, high humidity and illumination, powder X-ray diffraction (XRPD) results show that the vardos-isonicotin eutectic crystal form, the valdos-cinnamamide eutectic crystal form and the valdos-benzamide eutectic crystal form have good stability. The varactors-propionamide eutectic crystal form changes after being placed for 15 days under high temperature conditions, and is converted into varactors A crystal form.
On the other hand, according to the guidelines for the stability test of pharmaceutical preparations, long-term stability tests were conducted on the vardutasteride-isonicotinal co-crystal and the valdutasteride-benzamide co-crystal, and the results are shown in table 4.
Long-term stability experiments: and respectively taking a proper amount of crystal form samples, packaging by adopting PE and aluminum foil, placing in a constant temperature and humidity box with the RH of 60+/-5% at the temperature of 25+/-2 ℃, and then respectively taking about 100mg of the samples at the time of 0, 3, 6, 9 and 12 months, and testing the crystal form conditions by adopting powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
Table 4: stability data of 2 eutectic crystal forms of valdost under influence factor conditions
Figure PCTCN2021116336-APPB-000005
The results show that the vardos-isonicotin eutectic crystal form and the vardos-benzamide eutectic crystal form are not subjected to crystal transformation under each influence factor and have good stability after being placed for 12 months under the long-term stability test condition, and the powder X-ray diffraction (XRPD) results show that the vardos-isonicotin eutectic crystal form and the valdos-benzamide eutectic crystal form are not subjected to crystal transformation under each influence factor.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.

Claims (34)

  1. An X-ray powder diffraction pattern of a crystalline form of vardos-isonicotinc, comprising diffraction peaks at 2Θ angles of 14.24, 18.16, and 20.12 degrees.
  2. The crystalline form of vardos-isonicotin co-crystal according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2Θ angles of 7.68, 14.24, 15.27, 18.16, 20.12, and 30.43 degrees; or the crystalline form of the X-ray powder diffraction pattern comprises diffraction peaks at 7.68, 10.86, 14.24, 15.27, 18.16, 20.12, 25.84, 29.18, 29.52, 30.43, 31.23, 36.85 and 39.32 degrees 2θ; or an X-ray powder diffraction pattern of the crystalline form substantially as shown in figure 1.
  3. The crystalline form of vardutaster-isonicotin co-crystal according to claim 1 or 2, having a thermogravimetric analysis curve showing that said crystalline form has a weight loss of 0.5% -10.0% at 100 ℃ -200 ℃.
  4. A crystalline form of vardutaster-isonicotin co-crystal according to any one of claims 1-3, having a differential scanning calorimetry curve with an endothermic peak at 150-210 ℃.
  5. The co-crystalline form of varactors-isonicotins according to any one of claims 1-4, wherein the molar ratio of varactors to isonicotins is 1:1.
  6. A process for preparing the co-crystalline form of vardutaster-isonicotin of any one of claims 1-5, comprising: dissolving varactors in a solvent, adding isonicotin into the solution, stirring, filtering, and drying to constant weight to obtain varactors-isonicotin eutectic crystal forms.
  7. The method of claim 6, wherein the solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, and acetonitrile.
  8. The method according to claim 6 or 7, wherein the concentration of varactors after complete dissolution in solvent is between 5mg/ml and 300mg/ml.
  9. A process for preparing the co-crystalline form of vardutaster-isonicotin of any one of claims 1-5, comprising: dissolving vardost in a good solvent, adding isonicotin into the solution, adding the poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain the vardost-isonicotin eutectic crystal form.
  10. The method of claim 9, wherein the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether.
  11. The method of claim 9 or 10, wherein the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3.
  12. The method of any one of claims 9-11, wherein the concentration of varactors after complete dissolution in good solvent is between 5mg/ml and 300mg/ml.
  13. A crystalline form of varactors-benzamide co-crystals, the X-ray powder diffraction pattern of the crystalline form comprising diffraction peaks at 2Θ angles of 6.31, 21.12, and 24.18 degrees.
  14. The crystalline form of varactors-benzamide co-crystal of claim 13, wherein the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2Θ angles of 6.31, 15.58, 17.59, 21.12, 24.18, and 25.05 degrees; or the crystalline form of the X-ray powder diffraction pattern comprises diffraction peaks at 2θ angles 6.31,9.22, 10.41, 13.50, 14.98, 15.58, 17.59, 18.24, 18.99, 20.93, 21.12, 24.18, 25.05, 27.42, 27.91, 28.06, 33.63 and 36.51 degrees; or an X-ray powder diffraction pattern of the crystalline form substantially as shown in figure 5.
  15. The crystalline form of vardutaster-benzamide co-crystal of claim 13 or 14, having a thermogravimetric analysis curve showing that said crystalline form has a weight loss of 10.0% -70.0% at 50 ℃ -250 ℃.
  16. The crystalline form of varactors-benzamide co-crystal of any of claims 13-15, having a differential scanning calorimetry curve with an endotherm at 90-150 ℃.
  17. The co-crystal form of varactors-benzamide according to any of claims 13-16, wherein the molar ratio of varactors to benzamide is 1:2.
  18. A process for preparing the co-crystal form of varactors-benzamide of any one of claims 13-17 comprising: dissolving varactors in good solvent, adding benzamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-benzamide eutectic crystal form.
  19. The method of claim 18, wherein the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether.
  20. The method of claim 18 or 19, wherein the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:4.
  21. The method of any one of claims 18-20, wherein the concentration of varactors after complete dissolution in good solvent is 5mg/ml to 300mg/ml.
  22. An X-ray powder diffraction pattern of a crystalline form of varactors-cinnamamide comprising diffraction peaks at 2Θ angles of 4.24, 16.80, and 33.99 degrees.
  23. The co-crystal form of varactors-cinnamamide according to claim 22, wherein the X-ray powder diffraction pattern of the form comprises diffraction peaks at 2Θ angles of 4.24, 12.58, 16.80, 21.04, 29.62, and 33.99 degrees; or the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 4.24,8.38, 12.58, 14.14, 16.80, 20.18, 21.04, 25.32, 29.62, 33.99, 38.39 and 39.13 degrees 2θ; or an X-ray powder diffraction pattern of the crystalline form substantially as shown in figure 3.
  24. The crystalline form of vardutaster-cinnamamide co-crystal of claim 22 or 23, wherein thermogravimetric analysis shows that the crystalline form has a weight loss of 0.01% -1.5% at 120 ℃ -200 ℃.
  25. The crystalline form of vardutaster-cinnamamide co-crystal of any one of claims 22-24, having a differential scanning calorimetry curve with an endotherm at 120 ℃ -180 ℃.
  26. The co-crystal form of varactors-cinnamamide according to any one of claims 22-25, wherein the molar ratio of varactors to cinnamide is 1:1.
  27. A process for preparing the co-crystal form of varactors-cinnamamide according to any one of claims 22-26, comprising: dissolving varactors in a solvent, adding cinnamamide into the solution, stirring, filtering, and drying to constant weight to obtain varactors-cinnamamide eutectic crystal forms.
  28. The method of claim 27, wherein the solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile.
  29. The method of claim 27 or 28, wherein the concentration of varactors after complete dissolution in solvent is between 5mg/ml and 300mg/ml.
  30. A process for preparing the co-crystal form of varactors-cinnamamide according to any one of claims 22-26, comprising: dissolving varactors in good solvent, adding cinnamamide into the solution, adding poor solvent, stirring, separating out solid, filtering, and drying to constant weight to obtain varactors-cinnamamide eutectic crystal form.
  31. The method of claim 30, wherein the good solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, DMSO; the poor solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether.
  32. The method of claim 30 or 31, wherein the volume ratio of the good solvent to the poor solvent is from 1:1 to 1:3.
  33. The method of any one of claims 30-32, wherein the concentration of varactors after complete dissolution in good solvent is 5mg/ml to 300mg/ml.
  34. A composition, comprising: the crystalline form of any one of claims 1-5, claims 13-17, and claims 22-26 and a pharmaceutically acceptable adjuvant or carrier; wherein, according to the weight ratio, the crystal form is at least 90% of the valiroxostat, or the crystal form is not more than 0.5% -5% of the valiroxostat.
CN202180052769.6A 2020-09-04 2021-09-03 Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method thereof Pending CN115996720A (en)

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WO2015073779A1 (en) * 2013-11-15 2015-05-21 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
KR20190093651A (en) * 2016-12-13 2019-08-09 크리스탈 파마슈티컬 (쑤저우) 씨오., 엘티디. Novel crystalline forms of ((5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl) amino) acetic acid and preparation methods thereof
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