CN114105867A - 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 PDFInfo
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- CN114105867A CN114105867A CN202110987818.7A CN202110987818A CN114105867A CN 114105867 A CN114105867 A CN 114105867A CN 202110987818 A CN202110987818 A CN 202110987818A CN 114105867 A CN114105867 A CN 114105867A
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- 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
- A61P7/06—Antianaemics
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a crystal form of a hypoxia-inducible factor prolyl hydroxylase inhibitor and a preparation method thereof. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 14.26, 19.83 and 27.42 degrees, or comprising diffraction peaks at 2theta angles of 15.71, 22.28 and 26.42 degrees, or comprising diffraction peaks at 2theta angles of 16.72, 25.17 and 27.29 degrees, or comprising diffraction peaks at 2theta angles of 12.67, 15.95 and 20.42 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
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
Vacuostat (English name: Vadadustat, CAS number: 1000025-07-9) has a chemical name { [5- (3-chlorophenyl) -3-hydroxypyridine-2-carbonyl ] amino } acetic acid, is developed by Akebia, has a function of treating or preventing anemia, and has a mechanism of action of a Hypoxia Inducible Factor (HIF) prolyl hydroxylase inhibitor, which is in the third clinical stage as a medicine for treating anemia caused by secondary chronic kidney diseases; the structural formula is shown as the figure:
WO2015073779A1 of Akebia in original research discloses a crystalline form A, B, C of valdoxetase, wherein the crystalline form B can be converted into the crystalline form A in slurry at high temperature, the crystalline form A is a stable crystalline form, but the solubility of the crystalline form A in water is very poor, the crystallinity of the crystalline form B is poor, the stability is poor, the crystalline form C is difficult to reproduce by a conventional method, and the preparation condition and the reproducibility are harsh. Moreover, WO2015073779A1 did not perform much screening work on crystalline forms of Variostat.
Therefore, there remains a need in the art for a systematic and comprehensive development of different crystalline forms of valdoxat to find new crystalline forms and/or co-crystals more suitable for drug development.
Disclosure of Invention
Summary of The Invention
The invention provides a novel crystal form of valdoxat, a preparation method and a composition thereof.
In one aspect, the invention provides a crystalline form of valdoxat, referred to as a valdoxat-piperazine eutectic crystalline form. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 14.26, 19.83, and 27.42 degrees.
The thermogravimetric analysis curve shows that the crystal form has weight loss at 200-270 ℃ and the weight loss is 1.0-15.0%.
The differential scanning calorimetry curve of the crystal form has an endothermic peak at 200-260 ℃.
The invention also provides a method for preparing the eutectic crystal form of the kovastat-piperazine, which comprises the following steps: dissolving the valdoxetamol in a solvent, adding piperazine hexahydrate into the solution, stirring, filtering, and drying to constant weight to obtain the valdoxetamol-piperazine eutectic crystal form.
In one aspect, the invention provides a crystalline form of valdoxat, referred to as valdoxat-isoniazid co-crystal form I. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 15.71, 22.28, and 26.42 degrees.
The thermogravimetric analysis curve shows that the crystal form has weight loss at 120-200 ℃ and the weight loss is 0.1-2.5%.
The differential scanning calorimetry curve of the crystal form has an endothermic peak at 140-200 ℃.
The invention also provides a method for preparing the valdoxat-isoniazid eutectic crystal form I, which comprises the following steps: dissolving the valdoxetamol in a solvent, then adding isoniazid in the solution, separating out a white solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form I.
In one aspect, the invention provides a crystalline form of valdoxat, referred to as valdoxat-isoniazid co-crystal form II. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 16.72, 25.17, and 27.29 degrees.
The thermogravimetric analysis curve shows that the crystal form has weight loss at 120-200 ℃ and the weight loss is 0.1-1.5%.
The differential scanning calorimetry curve of the crystal form has an endothermic peak at 110-170 ℃.
The invention also provides a method for preparing the valdoxat-isoniazid eutectic crystal form II, which comprises the following steps: dissolving the valdoxetamol in a solvent, adding isoniazid into the solution, stirring, separating out a white solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form II.
In one aspect, the invention provides a crystalline form of valdoxat, referred to as valdoxat-isoniazid co-crystal form III. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 12.67, 15.95, and 20.42 degrees.
The thermogravimetric analysis curve shows that the crystal form has weight loss at 80-150 ℃, and the weight loss is 0.2-2.5%.
The differential scanning calorimetry curve of the crystal form has an endothermic peak at 80-150 ℃.
The invention also provides a method for preparing the valdoxat-isoniazid eutectic crystal form III, which comprises the following steps: and (3) placing the valdoxetast-isoniazid eutectic crystal I or the valdoxetast-isoniazid eutectic crystal II in a solvent for pulping, filtering and drying to constant weight to obtain the valdoxetast-isoniazid eutectic crystal III.
In one aspect, the present invention provides a crystalline form of valdoxat, referred to as valdoxat-p-toluenesulfonate. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 4.82, 16.75, and 22.78 degrees.
In one aspect, the present invention provides a crystalline form of valdoxat, referred to as valdoxat-camphorsulfonate. The crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 5.62, 18.81, and 29.57 degrees.
In another aspect, the present invention also provides a composition comprising any one or more of the foregoing crystalline forms of valdoxat. In some embodiments, the composition comprises at least 90% by mass of the crystalline form of vatacostat. In some embodiments, the crystalline form does not exceed 0.5% to 5% by mass of the composition of vatacostat.
Definition of terms
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
The term "crystal form" is used to describe the state of existence of a solid compound, describing the collection of various parameters of ionic, atomic or molecular composition, symmetry properties and periodic arrangement regularity within a crystal.
The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form, when the intensity of the first strong peak is defined as 100%.
The term "substantially as shown" 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 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.
The crystalline form has an X-ray powder diffraction peak whose measure of the 2theta or diffraction peak of the X-ray powder diffraction pattern has experimental error which may differ slightly between one machine and another and between one sample and another, the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units, and thus the value of the 2theta or diffraction peak cannot be considered absolute.
The Differential Scanning Calorimetry (DSC) curve of the crystal form has experimental errors, 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 numerical value of the experimental errors or differences may be 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
The thermogravimetric analysis (TGA) of the crystalline form has experimental errors, the temperature and amount of weight loss may differ slightly between one machine and another and between one sample and another, and the experimental error or difference may have a value of about +/-0.1 units, about +/-0.05 units, or about +/-0.01 units, so the values of the temperature and amount of weight loss cannot be considered absolute.
In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "approximately" is used, and there may be variations of ± 1%, ± 2%, or ± 5% in the numerical value of each number.
By "room temperature" is meant a temperature of about 15 ℃ to 32 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 28 ℃.
In the present invention, when the solid is dried, the solid is dried to a constant weight.
Detailed Description
The inventor develops the crystal form of the compound valdoxat and a preparation method thereof through research.
The crystalline form of the valdoxat provided by the invention is called as a valdoxat-piperazine eutectic crystalline form, a valdoxat-isoniazid eutectic crystalline form I, a valdoxat-isoniazid eutectic crystalline form II, a valdoxat-isoniazid eutectic crystalline form III, a valdoxat-p-toluenesulfonate or a valdoxat-camphorsulfonate, and the crystalline forms have good performance, high solubility and high bioavailability; or/and good in stability, is beneficial to storage, thereby meeting the requirement of drug stability; low hygroscopicity, good electrostatic performance, and is beneficial to operation in the production process.
In a first aspect, the present invention provides a new crystalline form of valdoxat, referred to as the eutectic crystalline form of valdoxat-piperazine.
The eutectic crystal form of the kovar staphylzine and the piperazine has the following characteristics: the X-ray powder diffraction pattern thereof contains diffraction peaks at 2theta angles of 14.26, 19.83 and 27.42 degrees.
In some embodiments, the eutectic crystalline form of valdoxetazin and piperazine has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 12.88, 14.26, 19.83, 21.68, 24.86, and 27.42 degrees.
In some embodiments, the eutectic crystalline form of valdoxetazin and piperazine has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 12.88, 14.26, 16.56, 16.75, 17.25, 19.58, 19.83, 20.40, 20.97, 21.68, 22.76, 23.20, 23.37, 24.00, 24.44, 24.86, 26.96, 27.42, 28.82, 29.62, and 29.97 degrees.
In some embodiments, the eutectic crystalline form of valdoxetazin and piperazine has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 12.88, 17.25, 20.97, 23.37, 27.42, and 29.97 degrees.
In some embodiments, the eutectic crystalline form of valdoxetazin and piperazine has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 14.26, 16.75, 19.58, 22.76, 24.86, and 29.62 degrees.
In some embodiments, the eutectic crystalline form of valdoxetazin and piperazine has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 16.56, 19.83, 21.68, 23.20, 24.00, and 28.82 degrees.
In some embodiments, the valdostat-piperazine eutectic crystalline form has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of the diffraction peaks at 2 Θ angles of 14.26, 19.83, and 27.42 degrees.
In some embodiments, the X-ray powder diffraction pattern of the eutectic crystalline form of valdostat-piperazine is substantially as shown in figure 1.
The eutectic crystal form of the kovaltastat and the piperazine is eutectic of the kovaltastat and the piperazine. In some embodiments, the molar ratio of the vatacostat to the piperazine is 1: 1.
The eutectic crystal form of the kovar staphylzine and the piperazine also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss at 200-270 ℃ and the weight loss is 1.0-15.0%. In some embodiments, the thermogravimetric analysis (TGA) curve shows that the crystalline form has a weight loss of about 7.7% at 200 ℃ to 270 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 2.
The eutectic crystal form of the kovar staphylzine and the piperazine also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 200-260 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 220 ℃ to 240 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endothermic peak at 227 ℃ to 237 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 230 ℃ to 234 ℃ with an endothermic peak top value of 232 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the eutectic crystal form of valdostat-piperazine is substantially as shown in figure 2.
In a second aspect, the invention provides a preparation method of the eutectic crystal form of the kovar staphylzine and piperazine.
The preparation method of the eutectic crystal form of the kovaltasol-piperazine is simple, convenient to operate, mild in condition, high in yield and purity and suitable for industrial production.
A method of preparing the eutectic crystalline form of vatacostat-piperazine, comprising: dissolving the valdoxetamol in a solvent, adding piperazine hexahydrate into the solution, stirring, filtering, and drying to constant weight to obtain the valdoxetamol-piperazine eutectic crystal form.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, methyl ethyl ketone, N-methyl pyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent is acetone.
In some embodiments, the concentration of the crystalline form of the eutectic of vatacostat-piperazine is 5mg/ml to 300mg/ml after the vatacostat is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after the valdoxat is completely dissolved in the solvent.
In a third aspect, the present invention provides a new crystalline form of valdoxat, referred to as valdoxat-isoniazid co-crystal form I.
The valdoxetamol-isoniazid eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern thereof contains diffraction peaks at 2theta angles of 15.71, 22.28 and 26.42 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form I has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 9.80, 15.71, 18.64, 22.28, 26.42, and 31.75 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form I has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.99, 7.69, 9.30, 9.80, 13.91, 15.71, 18.23, 18.64, 22.28, 24.65, 25.35, 26.42, 29.13, 29.64, 31.75, and 34.52 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form I has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 7.69, 15.71, 24.65, 25.35, 29.13, and 34.52 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form I has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 6.99, 9.80, 13.91, 18.23, 29.64, and 31.75 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form I has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 9.30, 18.23, 18.64, 22.28, 29.64, and 34.52 degrees.
In some embodiments, the valdostat-isoniazid co-crystal form I has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of the diffraction peaks at 2 Θ angles of 15.71, 22.28, and 26.42 degrees.
In some embodiments, the X-ray powder diffraction pattern of the eutectic crystalline form I of valdoxat-isoniazid is substantially as shown in figure 3.
The valdoxetamol-isoniazid eutectic crystal I is an eutectic of valdoxetamol and isoniazid. In some embodiments, the molar ratio of vardoxetastat to isoniazid is 1: 1.
The valdoxetamol-isoniazid eutectic crystal form I also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss of 0.1-2.5% at 120-200 ℃. In some embodiments, the thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 1.3% at 120 ℃ to 200 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 4.
The valdoxetamol-isoniazid eutectic crystal form I also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 140-200 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 155 ℃ to 185 ℃. In some embodiments, the crystalline form has an endotherm at 165 ℃ -169 ℃ differential scanning with an endotherm peak top value of 167 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the eutectic crystalline form I of valdoxat-isoniazid is substantially as shown in figure 4.
In a fourth aspect, the invention provides a preparation method of the valdoxat-isoniazid eutectic crystal form I.
The preparation method of the valdoxetasone-isoniazid eutectic crystal I is simple, convenient to operate, mild in condition, high in yield and purity and suitable for industrial production.
A method of preparing the valdoxat-isoniazid co-crystal form I comprising: dissolving the valdoxetamol in a solvent, then adding isoniazid in the solution, separating out a white solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form I.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent is acetone.
In some embodiments, the concentration of the valdoxat-isoniazid co-crystal form I is 5mg/ml to 300mg/ml after the valdoxat is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after the valdoxat is completely dissolved in the solvent.
In a fifth aspect, the present invention provides a new crystalline form of valdoxat, referred to as valdoxat-isoniazid eutectic crystalline form II.
The valdoxetamol-isoniazid eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern thereof contains diffraction peaks at 2theta angles of 16.72, 25.17 and 27.29 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 15.60, 16.72, 25.17, 26.11, 27.29, and 32.13 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 11.97, 12.33, 14.32, 15.60, 15.99, 16.72, 17.82, 19.67, 23.92, 25.17, 26.11, 27.29, 28.74, 29.47, 30.24 and 32.13 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 11.97, 12.33, 15.60, 16.72, 23.92, and 30.24 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 14.32, 17.82, 25.17, 26.11, and 29.47 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 15.99, 19.67, 27.29, 28.74, and 32.13 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form II has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of the diffraction peaks at 2 Θ angles of 16.72, 25.17, and 27.29 degrees.
In some embodiments, the X-ray powder diffraction pattern of valdoxat-isoniazid co-crystal form II is substantially as shown in figure 5.
The valdoxetamol-isoniazid eutectic crystal form II is an eutectic of valdoxetamol and isoniazid. In some embodiments, the molar ratio of vardoxetastat to isoniazid is 1: 1.
The valdoxetamol-isoniazid eutectic crystal form II also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss of 0.1-1.5% at 120-200 ℃. In some embodiments, the thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 0.45% at 120 ℃ to 200 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 6.
The valdoxetamol-isoniazid eutectic crystal form II also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 110-170 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 125 ℃ to 155 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endothermic peak at 132 ℃ to 146 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 137 ℃ to 141 ℃ with a peak top at 139 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the eutectic form II of valdoxat-isoniazid is substantially as shown in figure 6.
In a sixth aspect, the invention provides a preparation method of the valdoxat-isoniazid eutectic crystal form II.
The preparation method of the valdoxetasone-isoniazid eutectic crystal form II is simple, convenient to operate, mild in condition, high in yield and purity and suitable for industrial production.
A method of preparing the valdoxat-isoniazid co-crystal form II comprising: dissolving the valdoxetamol in a solvent, adding isoniazid into the solution, stirring, separating out a white solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form II.
In some embodiments, the solvent comprises at least one selected from the group consisting of ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO. In some embodiments, the solvent comprises ethyl acetate. In some embodiments, the solvent is ethyl acetate.
In some embodiments, the concentration of the valdoxat-isoniazid co-crystal form II is 5mg/ml to 300mg/ml after the valdoxat is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after the valdoxat is completely dissolved in the solvent.
In a seventh aspect, the present invention provides a new crystalline form of valdoxat, referred to as valdoxat-isoniazid co-crystal form III.
The valdoxetamol-isoniazid eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern thereof contains diffraction peaks at 2theta angles of 12.67, 15.95 and 20.42 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form III has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 12.67, 13.18, 14.63, 15.95, 16.78, and 20.42 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form III has the following properties: the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.32, 12.67, 13.18, 14.63, 15.95, 16.78, 18.32, 19.05, 19.40, 20.42, 22.94, 24.11, 25.62, 26.55, 27.80, 29.30 and 39.39 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form III has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 12.67, 13.18, 18.32, 19.05, 26.55, and 27.80 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form III has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 6.32, 14.63, 15.95, 19.40, 22.94, and 24.11 degrees.
In some embodiments, the valdoxat-isoniazid co-crystal form III has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 16.78, 20.42, 25.62, 29.30, and 39.39 degrees.
In some embodiments, the valdostat-isoniazid co-crystal form III has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of the diffraction peaks at 2 Θ angles of 12.67, 15.95, and 20.42 degrees.
In some embodiments, the X-ray powder diffraction pattern of valdoxat-isoniazid co-crystal form III is substantially as shown in figure 7.
The valdoxetamol-isoniazid eutectic crystal form III is an eutectic of valdoxetamol and isoniazid. In some embodiments, the molar ratio of vardoxetastat to isoniazid is 1: 1.
The valdoxetamol-isoniazid eutectic crystal form III also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss at 80-150 ℃ and the weight loss is 0.2-2.5%. In some embodiments, the thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 1.5% at 80 ℃ to 150 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 8.
The valdoxetamol-isoniazid eutectic crystal form III 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 crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 100 ℃ to 130 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of the crystalline form has an endothermic peak at 110 ℃ to 120 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 113 ℃ to 117 ℃ with an endothermic peak top value of 115 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the eutectic form III of valdoxat-isoniazid is substantially as shown in figure 8.
In an eighth aspect, the invention provides a preparation method of the eutectic crystal form III of valdoxat-isoniazid.
The preparation method of the valdoxetasone-isoniazid eutectic crystal form III is simple, convenient to operate, mild in condition, high in yield and purity and suitable for industrial production.
A method of preparing the valdoxat-isoniazid co-crystal form III comprising: and (3) placing the valdoxetast-isoniazid eutectic crystal I or the valdoxetast-isoniazid eutectic crystal II in a solvent for pulping, filtering and drying to constant weight to obtain the valdoxetast-isoniazid eutectic crystal III.
In some embodiments, the solvent comprises at least one selected from the group consisting of water, n-hexane, cyclohexane, n-heptane, diethyl ether, petroleum ether. In some embodiments, the solvent comprises water. In some embodiments, the solvent is water.
In some embodiments, the concentration of the valdoxat-isoniazid co-crystal form III is 5mg/ml to 300mg/ml after the valdoxat is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 10mg/ml to 50mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 20mg/ml to 100mg/ml after the valdoxat is completely dissolved in the solvent.
In a ninth aspect, the present invention provides a new crystalline form of valdoxat, referred to as valdoxat-p-toluenesulfonate.
In some embodiments, the valdoxat-p-toluenesulfonate salt has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2theta angles of 9.60, 13.69, 16.75, 17.80, 21.17, 22.78, and 32.38 degrees.
In some embodiments, the valdoxat-p-toluenesulfonate salt has the following characteristics: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 4.82, 8.35, 9.60, 13.69, 14.49, 16.75, 17.31, 17.80, 18.68, 19.40, 19.93, 21.17, 21.44, 22.78, 23.22, 23.72, 24.22, 26.44, 27.85, 28.02, 29.10, 30.49, 31.98, 32.38, 34.72, 35.04, 35.90, 37.71, and 38.42 degrees.
In some embodiments, the X-ray powder diffraction pattern of vatacostat-p-toluenesulfonate is substantially as shown in figure 9.
The valdoxetamol-p-toluenesulfonate is a salt form of valdoxetamol and p-toluenesulfonate. In some embodiments, the molar ratio of the vatacostat to the p-toluenesulfonate salt is 1: 1.
The said vardox-p-toluenesulfonate salt also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss at 100-160 ℃ and the weight loss is 1.0-6.0%. In some embodiments, the thermogravimetric analysis (TGA) curve shows that the crystalline form has a weight loss of about 3.2% at 100 ℃ to 160 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 10.
The said vardox-p-toluenesulfonate salt also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 110-170 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 130 ℃ to 150 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 137 ℃ to 141 ℃ with a peak top at 139 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the vatacostat-p-toluenesulfonate is substantially as shown in figure 10.
In a tenth aspect, the present invention provides a method for preparing said vatacoside-p-toluenesulfonate.
The preparation method of the vatacostat-p-toluenesulfonate provided by the invention is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.
A method of preparing the vatacostat-p-toluenesulfonate salt comprising: dissolving the vatacostat in a solvent, adding p-toluenesulfonic acid monohydrate, stirring, separating out a white solid, filtering, and drying to constant weight to obtain the vatacostat-p-toluenesulfonic acid salt.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, methyl ethyl ketone, N-methyl pyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO. In some embodiments, the solvent is acetone.
In some embodiments, the concentration of the salt of vardoxetasone-p-toluenesulfonate is from 5mg/ml to 300mg/ml after the valdoxetasone is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml after the valdoxat is completely dissolved in the solvent.
In an eleventh aspect, the present invention provides a new crystalline form of valdoxat, known as valdoxat-camphorsulfonate.
In some embodiments, the valdoxat-camphorsulfonate has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.62, 11.24, 13.93, 16.90, 18.81, 19.95, 22.60, 24.08, 24.66, and 29.57 degrees.
In some embodiments, the valdoxat-camphorsulfonate has the following properties: the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.19, 5.62, 9.97, 11.24, 13.93, 14.73, 15.61, 16.00, 16.47, 16.90, 18.21, 18.81, 19.95, 21.17, 21.44, 22.05, 22.60, 22.90, 24.08, 24.66, 25.24, 25.96, 26.30, 26.69, 28.81, 29.57, 30.28, 31.55, 32.98, 33.82, 34.19, 35.21, 36.83, and 38.11 degrees.
In some embodiments, the X-ray powder diffraction pattern of the salt of vatacoside-camphorsulfonic acid is substantially as shown in figure 11.
The valdoxetamol-camphorsulfonate is a salt form of valdoxetamol and camphorsulfonate. In some embodiments, the molar ratio of the vatacostat to the p-toluenesulfonate salt is 1: 1.
The said valdoxat-camphorsulfonate also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form has weight loss at 50-200 ℃ and the weight loss is 1.0-5.0%. In some embodiments, the thermogravimetric analysis (TGA) shows that the crystalline form has a weight loss of about 2.3% at 50 ℃ to 200 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in figure 12.
The said valdoxat-camphorsulfonate also has the following characteristics: the Differential Scanning Calorimetry (DSC) curve of the crystal form has an endothermic peak at 165-225 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 185 ℃ to 205 ℃. In some embodiments, the crystalline form has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 192 ℃ to 196 ℃ with an endothermic peak top value of 194 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of the vatacostat-camphorsulfonate salt is substantially as shown in figure 12.
In a twelfth aspect, the present invention provides a method for preparing said vatacoside-camphorsulfonate.
The preparation method of the vatacoside-camphorsulfonate is simple, convenient to operate, mild in condition, high in yield and purity and suitable for industrial production.
A process for preparing the said vatacoside-camphorsulfonate, comprising: dissolving the vatacostat in the solvent, adding the camphorsulfonic acid, stirring, precipitating a white solid, filtering, and drying to constant weight to obtain the vatacostat-camphorsulfonate.
In some embodiments, the solvent comprises at least one selected from the group consisting of acetone, methyl ethyl ketone, N-methyl pyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO. In some embodiments, the solvent is acetone.
In some embodiments, the concentration of the salt of valdoxat-camphorsulfonic acid is from 5mg/ml to 300mg/ml after the valdoxat is completely dissolved in the solvent during the preparation process. In some embodiments, the concentration is 5mg/ml to 200mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 100mg/ml when the valdoxat is completely dissolved in the solvent; in some embodiments, the concentration is 5mg/ml to 50mg/ml after the valdoxat is completely dissolved in the solvent.
In a thirteenth aspect, the present invention also provides a composition comprising any one of the aforementioned crystalline forms and/or salts of valproate.
In the composition, the crystal form or salt is at least 90% of the vardox, or the crystal form or salt is not more than 0.5% -5% of the vardox, by weight.
In some embodiments, the composition comprises: at least one of the aforementioned crystalline forms or salts, and a pharmaceutically acceptable adjuvant or carrier; wherein, according to the weight ratio, the crystal form or the salt is at least 90 percent of the vardox, or the crystal form or the salt is not more than 0.5 to 5 percent of the vardox.
In some embodiments, a composition comprises the aforementioned crystalline form of valdecoxist, wherein the crystalline form is at least 90% by weight of valdecoxist. In some embodiments, a composition comprises the aforementioned crystalline form of valdecoxist, wherein the crystalline form is at least 95%, or at least 99%, by weight. In some embodiments, a composition comprises the crystalline form of valdecoxist described above, wherein the crystalline form is at least 0.5% to 5% by weight of valdecoxist. In some embodiments, a composition comprises the aforementioned crystalline form of valdecoxist, wherein the crystalline form is at least 5% by weight of valdecoxist. In some embodiments, a composition comprises the foregoing crystalline form of valdecoxist, wherein the crystalline form is no more than 0.5% to 5% by weight of valdecoxist. In some embodiments, a composition comprises the foregoing crystalline form of valdecoxist, wherein the crystalline form is no more than 5% by weight of the valdecoxist.
In some embodiments, a composition comprises the aforementioned crystalline form of valtasol, which is at least one of a valtasol-piperazine eutectic crystalline form, a valtasol-isoniazid eutectic crystalline form I, a valtasol-isoniazid eutectic crystalline form II, a valtasol-isoniazid eutectic crystalline form III, a valtasol-p-toluenesulfonate salt, and a valtasol-camphorsulfonate salt. In some embodiments, a composition comprises the aforementioned crystalline form of valtasol, which is a valtasol-piperazine eutectic crystalline form, a valtasol-isoniazid eutectic crystalline form I, a valtasol-isoniazid eutectic crystalline form II, a valtasol-isoniazid eutectic crystalline form III, a valtasol-p-toluenesulfonate, and/or a valtasol-camphorsulfonate.
In some embodiments, a composition comprises at least one of the foregoing eutectic crystal form of vatuose-piperazine, eutectic crystal form I of vatuose-isoniazid, eutectic crystal form II of vatuose-isoniazid, eutectic crystal form III of vatuose-isoniazid, vatuose-p-toluenesulfonate, and vatuose-camphorsulfonate; wherein the crystalline form or salt is at least 90% of vatasstat, based on vatasstat. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatuosin-piperazine, eutectic crystal form I of vatuosin-isoniazid, eutectic crystal form II of vatuosin-isoniazid, eutectic crystal form III of vatuosin-isoniazid, vatuosin-p-toluenesulfonate, and/or vatuosin-camphorsulfonate, in a weight ratio, wherein the crystal form is at least 90% of vatuosin. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatinostat-piperazine, eutectic crystal form I of vatinostat-isoniazid, eutectic crystal form II of vatinostat-isoniazid, eutectic crystal form III of vatinostat-isoniazid, vatinostat-p-toluenesulfonate, and/or vatinostat-camphorsulfonate, in a weight ratio, wherein the crystal form is at least 95% or at least 99% of vatinostat.
In some embodiments, a composition comprises at least one of the foregoing eutectic crystal form of vatuose-piperazine, eutectic crystal form I of vatuose-isoniazid, eutectic crystal form II of vatuose-isoniazid, eutectic crystal form III of vatuose-isoniazid, vatuose-p-toluenesulfonate, and vatuose-camphorsulfonate; wherein the crystalline form or salt is at least 0.5% -5% of vatasstat calculated on a vatasstat basis. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatinostat-piperazine, eutectic crystal form I of vatinostat-isoniazid, eutectic crystal form II of vatinostat-isoniazid, eutectic crystal form III of vatinostat-isoniazid, vatinostat-p-toluenesulfonate, and/or vatinostat-camphorsulfonate, in a weight ratio, wherein said crystal form is at least 0.5% to 5% of vatinostat. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatinostat-piperazine, eutectic crystal form I of vatinostat-isoniazid, eutectic crystal form II of vatinostat-isoniazid, eutectic crystal form III of vatinostat-isoniazid, vatinostat-p-toluenesulfonate, and/or vatinostat-camphorsulfonate, in a weight ratio, wherein said crystal form is at least 5% of vatinostat. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatinostat-piperazine, eutectic crystal form I of vatinostat-isoniazid, eutectic crystal form II of vatinostat-isoniazid, eutectic crystal form III of vatinostat-isoniazid, vatinostat-p-toluenesulfonate and/or vatinostat-camphorsulfonate, in a weight ratio, wherein said crystal form is no more than 0.5% to 5% of vatinostat. In some embodiments, a composition comprises the foregoing eutectic crystal form of vatinostat-piperazine, eutectic crystal form I of vatinostat-isoniazid, eutectic crystal form II of vatinostat-isoniazid, eutectic crystal form III of vatinostat-isoniazid, castinostat-p-toluenesulfonate and/or varinostat-camphorsulfonate, in a weight ratio, wherein said crystal form is no more than 5% of vatinostat.
The composition can also comprise pharmaceutically acceptable auxiliary materials or carriers. The pharmaceutically acceptable auxiliary materials or carriers can comprise fillers, diluents, lubricants and the like. In some embodiments, the composition further comprises a pharmaceutically acceptable adjuvant or carrier, including 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, injections and the like.
Drawings
FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of a eutectic crystalline form of valdoxat-piperazine;
FIG. 2 shows a Differential Scanning Calorimetry (DSC) plot and a thermogravimetric analysis (TGA) plot of a eutectic crystal form of valbuterol-piperazine;
FIG. 3 shows an X-ray powder diffraction pattern (XRPD) of valdoxat-isoniazid co-crystal form I;
FIG. 4 shows a Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) plot of a eutectic crystalline form I of valacitretin-isoniazid;
FIG. 5 shows an X-ray powder diffraction pattern (XRPD) of valdoxat-isoniazid co-crystal form II;
FIG. 6 shows a Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) plot of a eutectic crystalline form II of valacitretin-isoniazid;
FIG. 7 shows an X-ray powder diffraction pattern (XRPD) of valdoxat-isoniazid co-crystal form III;
FIG. 8 shows a Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) plot of valsartan-isoniazid co-crystal form III;
FIG. 9 shows an X-ray powder diffraction pattern (XRPD) of valdoxat-p-toluenesulfonate;
FIG. 10 shows a Differential Scanning Calorimetry (DSC) plot and a thermogravimetric analysis (TGA) plot of valacitretin-p-toluenesulfonate;
FIG. 11 shows an X-ray powder diffraction pattern (XRPD) of valacitretin-camphorsulfonate;
FIG. 12 shows a Differential Scanning Calorimetry (DSC) plot and a thermogravimetric analysis (TGA) plot of valsartan-camphorsulfonate;
FIG. 13 shows an X-ray powder diffraction pattern (XRPD) of a eutectic crystal form of valsartan-piperazine after being placed under high temperature, high humidity and light conditions for 15 days (from bottom to top, 0 day, 15 days at high temperature, 15 days at high humidity and 15 days at light);
FIG. 14 shows X-ray powder diffraction patterns (XRPD) of a eutectic crystalline form I of valsartan-isoniazid after being placed under high temperature, high humidity and light for 15 days (from bottom to top, 0 day, 15 days at high temperature, 15 days at high humidity and 15 days light);
figure 15 shows an X-ray powder diffraction pattern (XRPD) of a eutectic crystalline form II of valsartan-isoniazid after being placed under high temperature, high humidity and light conditions for 15 days (from bottom to top, 0 day, 15 days at high temperature, 15 days at high humidity and 15 days light);
figure 16 shows an X-ray powder diffraction pattern (XRPD) of valtasol-isoniazid eutectic crystal form III before and after 15 days of storage at high temperature, high humidity, and under light (0 day, 15 days at high temperature, 15 days at high humidity, and 15 days under light, in that order from bottom to top);
FIG. 17 shows an X-ray powder diffraction pattern (XRPD) of valsartan-p-toluenesulfonate before and after being left under high temperature, high humidity and light for 15 days (0 day, 15 days at high temperature, 15 days at high humidity and 15 days at light for 15 days from bottom to top);
FIG. 18 shows an X-ray powder diffraction pattern (XRPD) of valsartan-camphorsulfonate after being left under high temperature, high humidity and light for 15 days (0 day, 15 days at high temperature, 15 days at high humidity and 15 days at light for 15 days from bottom to top).
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by methods known in the art or by methods described herein.
In the present invention, the temperature is in centigrade, mg is mg, mL is mL, h is hour, min is minute, DMF is N, N-dimethylformamide, and DMSO is dimethyl sulfoxide.
Parameters of the instrument
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 PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used is (Cu, K alpha, K alpha 1)
1.540598；Kα2
1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10 mm.a theta-theta continuous scanning mode is used to obtain an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data color, and Data was analyzed and presented using Data Viewer and HighScore Plus. In X-ray powderIn the diffraction pattern, the ordinate represents the diffraction intensity expressed in counts (counts), and the abscissa represents the diffraction angle 2 θ expressed in degrees (°).
Differential Scanning Calorimetry (DSC)
Using TA InstrumentsTMModel Q2000 was performed using a sealed disk apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the Heat Flow (W/g) released per unit mass of a substance.
Thermogravimetric analysis (TGA)
TGA measurements in TA InstrumentsTMIn model Q500. The operation steps are that the empty crucible is peeled, about 10mg of solid sample is taken and put in the peeled empty crucible, and the solid sample is spread evenly. After the instrument runs stably, data are collected at a heating rate of 10 ℃/min between room temperature and 300 ℃ under nitrogen purging, and a spectrum is recorded. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents mass percent (Weight%).
Preparation of Vadadustat-piperazine eutectic
Example 1
150mg of the crude Vadadustat product (in solid form, but not limited thereto) was added to 5ml of acetone solvent, stirred at room temperature to obtain a clear solution, then 97.12mg of piperazine hexahydrate was slowly added, stirred for half an hour to precipitate a white solid, filtered, and placed in a drying oven to be dried under vacuum at 50 ℃ for 24 hours to obtain about 150mg of a white solid. The X-ray powder diffraction pattern is determined to be basically consistent with that of figure 1, and the DSC and TGA patterns are determined to be basically consistent with that of figure 2.
Preparation of Vadadustat-isoniazid eutectic crystal form I
Example 2
150mg of the crude Vadadustat product (in the form of a solid, but not limited thereto) was added to 5ml of an acetone solvent, and after stirring at room temperature, a clear solution was obtained, 68.57mg of isoniazid was slowly added to precipitate a white solid, which was then filtered off with suction and placed in a drying oven for vacuum drying at 50 ℃ for 24 hours to obtain about 140mg of a white solid. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 3, and the DSC and TGA patterns were determined to be substantially in accordance with figure 4.
Preparation of Vadadustat-isoniazid eutectic crystal form II
Example 3
150mg of Vadadustat crude product (in a solid form without limitation) is added into 5ml of ethyl acetate solvent, heated to 50 ℃, stirred to obtain a clear solution, then added with 68.57mg of isoniazid slowly, cooled to room temperature, stirred for one day to separate out a white solid, filtered, placed in a drying oven, and dried in vacuum at 50 ℃ for 24 hours to obtain about 140mg of the white solid. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 5, and the DSC and TGA patterns were determined to be substantially in accordance with figure 6.
Preparation of Vadadustat-isoniazid eutectic crystal form III
Example 4
820mg of Vadadustat-isoniazid eutectic crystal form II crude product is added into 20ml of pure water for pulping for 24 hours, is filtered, is placed in a drying oven for vacuum drying at 50 ℃ for 24 hours, and obtains about 390mg of white solid. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 7, and the DSC and TGA patterns were determined to be substantially in accordance with figure 8.
Preparation of Vadadustat-p-toluenesulfonate salt
Example 5
150mg of the crude Vadadustat product (in solid form, but not limited thereto) is added to 5ml of an acetone solvent, stirred at room temperature to obtain a clear solution, 95mg of p-toluenesulfonic acid monohydrate is slowly added, stirred for half an hour to precipitate a white solid, and the white solid is subjected to suction filtration and placed in a drying oven to be dried in vacuum at 50 ℃ for 24 hours to obtain about 140mg of the white solid. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 9, and the DSC and TGA patterns were determined to be substantially in accordance with figure 10.
Preparation of Vadadustat-camphorsulfonate
Example 6
150mg of the crude Vadadustat product (in solid form, but not limited thereto) was added to 5ml of acetone solvent, stirred at room temperature to obtain a clear solution, then 116mg of camphorsulfonic acid was slowly added, stirred for half an hour to precipitate a white solid, which was filtered off with suction and placed in a drying oven for vacuum drying at 50 ℃ for 24 hours to obtain about 140mg of a white solid. The X-ray powder diffraction pattern was determined to be substantially in accordance with figure 11, and the DSC and TGA patterns were determined to be substantially in accordance with figure 12.
Example 7 solubility testing
Experiments are designed according to the guiding principle of the solubility test of the current Chinese pharmacopoeia, and the solubility of 7 crystal forms of the kovar staphyl in pure water at 37 ℃ is respectively measured, and the results are shown in table 1. The results show that the solubility of the four co-crystals is significantly higher than that of the kovar staphyline form a, wherein: the solubility of the eutectic crystal form of the koxistat-piperazine is the maximum and is 54 times of that of the koxistat crystal form A; the solubilities of the valdoxat-isoniazid eutectic crystal I, the valdoxat-isoniazid eutectic crystal II and the valdoxat-isoniazid eutectic crystal III are respectively 3.3 times, 4.4 times and 2.9 times of that of the valdoxat.
Table 1: solubility data for 7 crystalline forms of Vascustat (37 ℃, water)
| Sample (I) | Solubility (in Vat. sup. stat, mg/ml) |
| Vasculatastat form A | 0.0271 |
| Crystalline form of valdoxetazin-piperazine | 1.4504 |
| Vaxostat-isoniazid eutectic crystal form I | 0.0901 |
| Vaxostat-isoniazid eutectic crystal form II | 0.1192 |
| Vaxostat-isoniazid eutectic crystal form III | 0.0802 |
| Vat-p-Toluenesulfonic acid | 0.0016 |
| Vat-doxetamol-camphorsulfonic acid | 0.0017 |
Example 8 stability study
According to the guiding principle of the stability test of the pharmaceutical preparation, the influence factor experiment including a high temperature test, a high humidity test and a strong light irradiation test is carried out on the crystal form of the valdox, and the stability condition influencing the crystal form is investigated, as shown in the following table 2.
High-temperature test: taking a proper amount of crystal form samples respectively, flatly spreading the crystal form samples in a weighing bottle, placing the crystal form samples in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, then taking about 100mg of the samples respectively in 0, 5 and 15 days, and testing the crystal form conditions of the samples by powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
High humidity test: taking a proper amount of crystal form samples respectively, flatly spreading the crystal form samples in a weighing bottle, placing the crystal form samples in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, taking about 100mg of the samples respectively in 0, 5 and 15 days, and testing the crystal form conditions of the samples by powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
And (3) illumination test: taking a proper amount of crystal form samples respectively, spreading the crystal form samples into weighing bottles, placing the samples in a constant temperature and humidity box (25 ℃, RH 60% +/-5%) with visible light 4500Lux +/-500 Lux (VIS) and ultraviolet light 1.7W X h/m2(UV), taking about 100mg of the samples respectively in 0, 5 and 15 days, and testing the crystal form conditions of the samples by powder X-ray powder diffraction (XRPD) and Differential Scanning Calorimetry (DSC).
Table 2: stability data of 6 crystal forms of Vascustat under influence factor conditions
And (4) conclusion: powder X-ray diffraction (XRPD) results of four eutectic samples, namely a valtasol-piperazine eutectic, a valtasol-isoniazid crystal form I, a valtasol-isoniazid crystal form II and a valtasol-isoniazid crystal form III, after being placed for 15 days under test conditions of three influence factors, namely high temperature, high humidity and illumination show that crystal transformation does not occur under each influence factor, and the eutectic has good stability. The XRD of the salt of valtasol-camphorsulfonic acid changed after being left under high humidity conditions for 15 days, and a small amount of camphorsulfonic acid appeared.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (21)
1. A crystalline form of a co-crystal of vatuostat-piperazine having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 14.26, 19.83, and 27.42 degrees.
2. The crystalline form of vatacostat-piperazine co-crystal of claim 1, wherein an X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2 Θ angles of 12.88, 14.26, 19.83, 21.68, 24.86, and 27.42 degrees; or an X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2 Θ angles of 12.88, 14.26, 16.56, 16.75, 17.25, 19.58, 19.83, 20.40, 20.97, 21.68, 22.76, 23.20, 23.37, 24.00, 24.44, 24.86, 26.96, 27.42, 28.82, 29.62, and 29.97 degrees; or an X-ray powder diffraction pattern of said crystalline form substantially as shown in figure 1.
3. The eutectic crystal form of vatacos-piperazine according to claim 1 or 2, wherein the thermogravimetric analysis curve shows that the crystal form has a weight loss at 200 ℃ -270 ℃, and the weight loss amount is 1.0% -15.0%; or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 200-260 ℃; or the molar ratio of the valdoxetamol to the piperazine is 1: 1.
4. A method of preparing the eutectic crystalline form of valdoxat-piperazine of any of claims 1-3, comprising: dissolving the valdoxetamol in a solvent, adding piperazine hexahydrate into the solution, stirring, filtering, and drying to constant weight to obtain the valdoxetamol-piperazine eutectic crystal form.
5. The method of claim 4, the solvent comprising at least one selected from the group consisting of acetone, methyl ethyl ketone, N-methyl pyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, N-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO; the concentration of the vardoxetastat is 5mg/ml-300mg/ml after the vardox is completely dissolved in the solvent.
6. A crystalline form I of valdoxat-isoniazid co-crystal having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 15.71, 22.28 and 26.42 degrees.
7. The crystalline form I of valdoxat-isoniazid co-crystal of claim 6 wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 θ angles of 9.80, 15.71, 18.64, 22.28, 26.42 and 31.75 degrees; or an X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2 Θ angles of 6.99, 7.69, 9.30, 9.80, 13.91, 15.71, 18.23, 18.64, 22.28, 24.65, 25.35, 26.42, 29.13, 29.64, 31.75, and 34.52 degrees; or an X-ray powder diffraction pattern of said crystalline form substantially as shown in figure 3.
8. The vatacostat-isoniazid eutectic crystal form I according to claim 6 or 7, wherein a thermogravimetric analysis curve shows that the crystal form has weight loss at 120-200 ℃ and the weight loss is 0.1-2.5%; or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 140-200 ℃; or the molar ratio of the vardoxetastat to the isoniazid is 1: 1.
9. A method of preparing the valdoxat-isoniazid co-crystal form I of any one of claims 6 to 8 comprising: dissolving the valdoxetamol in a solvent, then adding isoniazid into the solution, separating out a solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form I.
10. The method of claim 9, the solvent comprising at least one selected from the group consisting of acetone, butanone, N-methylpyrrolidone, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO; or the concentration of the vardoxetastat is 5mg/ml-300mg/ml after the vardox is completely dissolved in the solvent.
11. A crystalline form II of valdoxat-isoniazid co-crystal having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 16.72, 25.17 and 27.29 degrees.
12. The crystalline form II of vatuzosin-isoniazid according to claim 11 wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 15.60, 16.72, 25.17, 26.11, 27.29 and 32.13 degrees; or the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks with 2theta angles of 11.97, 12.33, 14.32, 15.60, 15.99, 16.72, 17.82, 19.67, 23.92, 25.17, 26.11, 27.29, 28.74, 29.47, 30.24, 32.13 degrees; or an X-ray powder diffraction pattern of said crystalline form substantially as shown in figure 5.
13. The vatacostat-isoniazid eutectic crystal form II according to claim 10 or 11, wherein a thermogravimetric analysis curve shows that the crystal form has weight loss at 120-200 ℃ and the weight loss amount is 0.1-1.5%; or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 110-170 ℃; or the molar ratio of the vardoxetastat to the isoniazid is 1: 1.
14. A method of preparing the valdoxat-isoniazid co-crystal form II of any one of claims 11-13 comprising: dissolving the valdoxetamol in a solvent, then adding isoniazid into the solution, stirring, separating out a solid, filtering, and drying to constant weight to obtain the valdoxetamol-isoniazid eutectic crystal form II.
15. The method of claim 14, the solvent comprising at least one selected from the group consisting of ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran, acetonitrile, DMF, DMSO; or the concentration of the vardoxetastat is 5mg/ml-300mg/ml after the vardox is completely dissolved in the solvent.
16. A crystalline form III of valdoxat-isoniazid co-crystal having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 12.67, 15.95 and 20.42 degrees.
17. The valdoxat-isoniazid co-crystal form III of claim 16 wherein the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 12.67, 13.18, 14.63, 15.95, 16.78, and 20.42 degrees; or the X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2 Θ angles of 6.32, 12.67, 13.18, 14.63, 15.95, 16.78, 18.32, 19.05, 19.40, 20.42, 22.94, 24.11, 25.62, 26.55, 27.80, 29.30, 39.39 degrees; or an X-ray powder diffraction pattern of said crystalline form substantially as shown in figure 7.
18. The vatacostat-isoniazid eutectic crystal form III according to claim 15 or 16, wherein a thermogravimetric analysis curve shows that the crystal form has weight loss at 80-150 ℃ of 0.2-2.5%; or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 80-150 ℃; or the molar ratio of the vardoxetastat to the isoniazid is 1: 1.
19. A method of preparing the valdoxat-isoniazid co-crystal form III of any of claims 16-18 comprising: placing the crystalline form I of the valdoxus-isoniazid eutectic of any one of claims 6 to 8 or the crystalline form II of the valdoxus-isoniazid eutectic of any one of claims 11 to 13 in a solvent, pulping, filtering, and drying to constant weight to obtain the crystalline form III of the valdoxus-isoniazid eutectic.
20. The method of claim 19, the solvent comprising at least one selected from the group consisting of water, n-hexane, cyclohexane, n-heptane, diethyl ether, petroleum ether; or the concentration of the vardoxetastat is 5mg/ml-300mg/ml after the vardox is completely dissolved in the solvent.
21. A composition, comprising: a crystalline form as claimed in any one of claims 1 to 3, claims 6 to 8, claims 11 to 13 and claims 16 to 18 and a pharmaceutically acceptable adjuvant or carrier; wherein, according to the weight ratio, the crystal form is at least 90% of the kovatat, or the crystal form is not more than 0.5% -5% of the kovatat.
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