CN115141143A - Crystal form of acid and preparation method thereof - Google Patents

Abstract

The invention provides a crystal form of acid and a preparation method thereof, belonging to the technical field of medicines. The crystal form provided by the invention has better stability and solubility, and can be applied to pharmaceutical preparations.

Description

Crystal form of acid and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a crystal form of acid and a preparation method thereof.

Background

The compound desdoxtat (Desidustat), which has the structure shown below, is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and is currently in clinical trials for the treatment of anemia arising from Chronic Kidney Disease (CKD).

The structure and preparation method of the Dedossier are disclosed in documents CN104903295B and the like, but specific morphological information of the obtained product is not disclosed, and one crystal form of the Dedossier is disclosed in U.S. patent application US20190359574, but the existence of other crystal forms and related performance information of possible crystal forms are not disclosed.

Because the crystal form of the drug has important influence on the preparation of the drug, the preparation, the storage, the application, the dissolution, the bioavailability and the like of the pharmaceutical preparation, different crystal forms may have differences in various aspects, and the problems that the drug effect, the safety and the application of the pharmaceutical preparation are obviously different or the quality requirements are not easily met are caused, so the crystal form of the drug needs to be researched. The inventor conducts related research on the crystal form of the doxycycline and discovers a novel crystal form which can be applied.

Disclosure of Invention

Summary of The Invention

The present invention relates generally to a novel crystalline form of the compound desdoxicator. Part of the new crystal forms provided by the invention have the characteristics of stability and convenience for implementation and application.

On the other hand, the invention also provides a preparation method of the novel crystal form, a pharmaceutical composition and the like.

Definition of terms

The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, and so on), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

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 "substantially as shown in the figure" means that substantially pure certain "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, some diffraction peaks in an X-ray powder diffraction pattern of the sample, which are attributed to the crystal form, may be reduced due to the detection sensitivity of an instrument.

The term "relative intensity" refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form is defined as 100%.

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 X-ray powder diffraction peak of the crystal, the 2theta or the measurement of the diffraction peak of the X-ray powder diffraction pattern of which has experimental error, may be slightly different between one machine and another machine and between one sample and another, the 2theta or the measurement of the diffraction peak of the X-ray powder diffraction pattern being ± 0.2 °, so that the value of the 2theta or the diffraction peak cannot be regarded as absolute.

The Differential Scanning Calorimetry (DSC) curve of the crystal has experimental errors, the position and peak value of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so that the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, the endothermic curve or the weight loss rate may slightly differ between one machine and another and between one sample and another, the numerical value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, and thus the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as 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 a variation of +/-1%, +/-2%, +/-3%, +/-4%, or +/-5% between each number based on the disclosed numbers. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.

By "room temperature" is meant a temperature of from about 20 ℃ to 35 ℃ or from about 23 ℃ to 28 ℃ or about 25 ℃.

The term "good solvent" can be a single solvent or a mixture of solvents, and refers to a sample having a solubility in the single solvent or mixture of solvents of greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L. In some embodiments, the sample has greater solubility in the good solvent than the anti-solvent; in some embodiments, the difference in solubility of the good solvent and the anti-solvent for the sample is about 10%,20%,30%,40%,50%,60%,70%,80%, or 90%; in some embodiments, the good solvent is more soluble in the sample than the anti-solvent, greater than 10%,20%,30%,40%,50%,60%,70%,80%, or 90%.

In the present invention, the form of destrostat disclosed in U.S. patent application No. US20190359574 is referred to as form α, which XRPD has diffraction peaks at 2 θ (units: degrees, °) of 8.0,8.9,10.6,11.3,16.1,25.5 and 26.4 degrees.

Detailed Description

In one aspect, the inventors have developed through research novel crystalline forms of doxycycline, including: form a, form B, form C, form D-1, form E, form F, form G, form H and form I.

A crystalline form of descemet, designated form a, having an X-ray powder diffraction pattern having diffraction peaks at 10.31, 11.25, 14.74, 17.53, 19.02, 21.28, 21.70, 22.57, 27.05 and 28.23 degrees 2 Θ (units: degrees, °, error ± 0.2 °).

In some embodiments, the form a has an X-ray powder diffraction pattern having diffraction peaks at 10.31, 11.25, 14.74, 17.53, 19.02, 19.75, 21.28, 21.70, 22.57, 24.53, 27.05, 28.23, 34.56, and 38.54 degrees 2 Θ.

In some embodiments, form a has an X-ray powder diffraction pattern having diffraction peaks at 10.31, 11.25, 14.06, 14.74, 17.53, 18.21, 19.02, 19.75, 21.28, 21.70, 22.57, 23.27, 24.53, 25.83, 27.05, 28.23, 29.66, 30.15, 34.56, and 38.54 degrees 2 Θ.

In some embodiments, form a has an X-ray powder diffraction (XRPD) pattern as shown in figure 1.

The crystal form A also has the following characteristics that an endothermic peak is provided in a Differential Scanning Calorimetry (DSC) curve in the range of 208-218 ℃. In some embodiments, form a has an endothermic peak at 213 ℃ to 217 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, form a has an endothermic peak at 211 ℃ to 215 ℃ in a Differential Scanning Calorimetry (DSC) curve with a peak top value of 216 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form a is shown in figure 2.

The thermogravimetric analysis (TGA) of form a shows no weight loss below 200 ℃. According to the TGA of form a, said form a is considered to be an anhydrous form, a non-solvate.

In some embodiments, the thermogravimetric analysis curve (TGA) of form a is as shown in figure 3.

According to the experimental study on the stability of influencing factors, the crystal form A is a stable crystal form, is stable under the conditions of high temperature, high humidity or illumination, and cannot generate crystal form transformation. According to the performance research experiment result of the crystal form A, the crystal form A is not easy to absorb moisture and is more competitive compared with the known crystal form.

In another aspect, the present invention provides a process for preparing said form a.

In some embodiments, a process for preparing the crystalline form a of dolostone comprises: dissolving the delta in a crystallization solvent, then cooling to precipitate crystals, filtering, and removing the solvent to obtain a crystal form A; the crystallization solvent is at least one of isobutanol, ethyl acetate and acetonitrile. The mass-to-volume ratio of the descaler to the crystallization solvent may be from 10mg to 1100mg. In some embodiments, the desostat is dissolved in the crystallization solvent under heating, which may be at a temperature of 20 ℃ to 80 ℃. In some embodiments, the solution is cooled to-10 ℃ to 25 ℃ to precipitate crystals. In some embodiments, the solution is cooled to-10 ℃ to 15 ℃ to precipitate crystals. In some embodiments, the solution is cooled to-5 ℃ to 10 ℃ to precipitate crystals. In some embodiments, the solution is cooled to-10 ℃,5 ℃,0 ℃,5 ℃ or 10 ℃ to precipitate crystals.

In some embodiments, a method of preparing form a of dolastatin, comprising: dissolving the Dedoxetastat in a good solvent, mixing the solution with an anti-solvent after the solution is clear, separating out crystals, filtering, and removing the solvent to obtain a crystal form A; the good solvent is glycol dimethyl ether or N, N-dimethylacetamide or the combination thereof; the anti-solvent is ethanol or isopropanol or a combination thereof. The mass-volume ratio of the desdoxetas to the good solvent is 5 mg. The volume ratio of the anti-solvent to the good solvent can be 1. The temperature of the precipitated crystal can be controlled to be-5-50 ℃, preferably-5-25 ℃. In some embodiments, the temperature at which crystals precipitate is from-5 ℃ to 10 ℃ or from-5 ℃ to 5 ℃. In some embodiments, the anti-solvent is added to a solution of the dedospitab and the good solvent.

In some embodiments, a method of preparing form a of dolastatin, comprising: mixing the descales with a solvent, suspending and stirring at 20-80 ℃ for 20 hours or more, filtering, and removing the solvent to obtain a crystal form A; the solvent is at least one of water, methanol, ethanol, isopropanol, n-butanol, acetone, butanone, methyl isobutyl ketone, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetonitrile, isopropyl ether and methyl tert-butyl ether. In some embodiments, the suspension is stirred at 40 ℃ to 70 ℃ for 20 hours to 48 hours. The mass-volume ratio of the dedospitab to the solvent can be 1mg. In some embodiments, a method of preparing form a of dolastatin, comprising: mixing the Dedostat with water, ethanol or a combined solvent thereof, suspending and stirring at 40-70 ℃ for 20-48 hours, filtering, and removing the solvent to obtain the crystal form A.

In some embodiments, a method of preparing form a of dolastatin, comprising: dissolving the desdox in a solvent, and volatilizing the solvent at the temperature of 20-80 ℃ to obtain a crystal form A; the solvent is ethylene glycol dimethyl ether. The mass volume ratio of the descales to the solvent may be from 10mg to 1200mg.

In another aspect, a new form of dolostone is designated form B.

Form B of descaler having an X-ray powder diffraction pattern with diffraction peaks at 2 θ (units: degrees, °, error ± 0.2 °) of 7.81, 10.20, 11.09, 16.19, 18.47, 22.45, 23.67 and 26.95 degrees.

In some embodiments, the form B has an X-ray powder diffraction pattern having diffraction peaks at 7.81, 10.20, 11.09, 14.62, 15.70, 16.19, 18.47, 18.89, 22.45, 23.67, and 26.95 degrees 2 Θ.

In some embodiments, the form B has an X-ray powder diffraction pattern having diffraction peaks at 7.81, 10.20, 11.09, 13.11, 14.62, 15.70, 16.19, 18.47, 18.89, 19.74, 21.14, 22.06, 22.45, 23.67, 26.95, 27.83, and 28.11 degrees 2 Θ.

In some embodiments, the form B has an X-ray powder diffraction (XRPD) pattern as shown in figure 4.

The Differential Scanning Calorimetry (DSC) curve of the crystal form B has an endothermic peak in the range of 210-220 ℃, and the peak top value is 214 ℃.

In some embodiments, the thermogravimetric analysis curve (TGA) of form B has a weight loss of more than 5% over the range of 30 ℃ to 120 ℃. In some embodiments, the thermogravimetric analysis curve (TGA) of form B has a weight loss of about 8.18% over the range of 30 ℃ to 120 ℃. Form B is considered a solvate according to its TGA results. In some embodiments, the form B is a solvate of desdox 1, 4-dioxane having a mole ratio of desdox to 1, 4-dioxane of 1.

A method of preparing form B comprising: mixing the Dedostat and the 1, 4-dioxane, suspending and stirring, filtering, and drying to obtain a crystal form B; or comprises the following steps: mixing the desdoxetane with at least one of N, N-dimethylformamide, N-dimethylacetamide and 1, 4-dioxane, wherein the volume ratio of the 1, 4-dioxane to another solvent is 15-1; or comprises the following steps: mixing the Dedoxetastat with 1, 4-dioxane to dissolve the solid to obtain a solution, then cooling to-10 ℃, crystallizing, filtering, and drying to obtain the crystal form B. In the process for preparing form B, the mass to volume ratio of desdoxat to solvent may be from 10mg to 150mg.

The inventors have studied and developed a new form of doxycycline, called form C. Form C has diffraction peaks at positions where 2 θ (unit: degree, °, error ± 0.2 °) is 6.49,9.25, 10.55, 11.22, 16.19, 16.35, 17.63, 18.61, 19.62, 19.87 and 24.19 degrees in an X-ray powder diffraction pattern.

In some embodiments, form C has an X-ray powder diffraction pattern with diffraction peaks at 6.49,7.60,9.25, 10.55, 11.22, 16.19, 16.35, 17.63, 18.61, 19.62, 19.87, 21.58, 22.59, 23.02, and 24.19 degrees 2 Θ.

In some embodiments, form C has an X-ray powder diffraction pattern having diffraction peaks at positions 6.49,7.60,9.25, 10.55, 11.22, 12.60, 15.27, 16.19, 16.35, 17.63, 18.61, 19.62, 19.87, 21.58, 22.59, 23.02, 23.63, 24.19, 26.27, and 26.92 degrees 2 Θ.

In some embodiments, form C has an X-ray powder diffraction (XRPD) pattern as shown in figure 5.

A method of making form C comprising: dissolving the Dedoxetastat in N, N-dimethylformamide or in N, N-dimethylformamide and butanone or in a mixed solvent of N, N-dimethylformamide and methyl isobutyl ketone, and volatilizing to remove the solvent to obtain a crystal form C; the volume ratio of the descales to the solvent can be 10mg to 1ml to 100mg; the temperature for volatilizing and removing the solvent can be 40-80 ℃.

A method of preparing form C comprising: suspending and stirring the desdox and a mixed solvent of N, N-dimethylformamide and isopropyl acetate at 20-50 ℃ for 20-24 hours, then filtering, and removing the solvent to obtain a crystal form C; the volume ratio of descaler to solvent used may be from 10mg to 150mg.

A method of preparing form C comprising: dissolving the desdox in N, N-dimethylformamide, mixing with an anti-solvent, crystallizing, and filtering to obtain a crystal form C; the anti-solvent may be at least one of methyl tert-butyl ether, ethanol, isopropanol, butanone, butyl formate and isopropyl acetate. The volume ratio of the antisolvent to N, N-dimethylformamide may be from 0.5. The mass-volume ratio of the dedocestat to the N, N-dimethylformamide can be 60mg.

The inventors have studied and developed a new form of doxicator, called form D. Form D has an X-ray powder diffraction pattern having diffraction peaks at positions 2 θ (unit: degree, error ± 0.2 °) of 7.36, 11.19, 14.73 and 22.16 degrees.

In some embodiments, form D has an X-ray powder diffraction pattern having diffraction peaks at 7.36, 11.19, 14.73, 15.19, 18.82, and 22.16 degrees 2 Θ.

In some embodiments, form D has an X-ray powder diffraction pattern having diffraction peaks at 7.36, 11.19, 14.73, 15.19, 18.47, 18.82, 22.16, and 25.69 degrees 2 Θ.

In some embodiments, form D has an X-ray powder diffraction (XRPD) pattern as shown in figure 6.

In some embodiments, the crystalline form D is obtained by dissolving dedospitab in dimethyl carbonate, cooling to-10 ℃ to 15 ℃, and crystallizing; the mass-volume ratio of the dedospitab to the dimethyl carbonate can be 1mg.

The inventor researches and develops a new crystal form of the Dedossier, namely the crystal form D-1. An X-ray powder diffraction pattern of form D-1 has diffraction peaks at 11.12, 14.61, 18.89, 21.15, 22.44, 26.91 and 28.10 degrees 2theta (units: degrees, °, error ± 0.2 ℃).

In some embodiments, the crystalline form D-1 has an X-ray powder diffraction pattern having diffraction peaks, in terms of 2 Θ, at 10.17, 11.12, 14.61, 17.42, 18.89, 21.15, 22.44, 24.40, 26.91, and 28.10 degrees.

In some embodiments, the crystalline form D-1 has an X-ray powder diffraction pattern having diffraction peaks, in terms of 2 Θ, at 10.17, 11.12, 14.61, 17.42, 18.89, 21.15, 21.57, 22.44, 24.40, 26.91, 27.43, 28.10, 29.53, 30.01, 34.43, and 38.41 degrees.

In some embodiments, the crystalline form D-1 has an X-ray powder diffraction (XRPD) pattern as shown in figure 7.

The crystal form D-1 also has the following characteristics that an endothermic peak is provided in a Differential Scanning Calorimetry (DSC) curve in the range of 210-218 ℃. In some embodiments, form D-1 has an endothermic peak at 210 ℃ to 216 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, form D-1 has an endothermic peak at 211 ℃ to 216 ℃ in a Differential Scanning Calorimetry (DSC) curve with a peak top value of 215 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form D-1 is shown in figure 8.

The thermogravimetric analysis curve (TGA) of said crystalline form D-1 shows substantially no weight loss below 200 ℃. According to the TGA of form D-1, said form D-1 is considered to be an anhydrous form, a non-solvate.

In some embodiments, the thermogravimetric analysis curve (TGA) of form D-1 is shown in figure 9.

A method of preparing form D-1, comprising: and (3) drying the crystal form D for 12-24 hours in vacuum at the temperature of 40-80 ℃ to obtain the crystal form D-1.

The inventors have also developed a new form of dedospitabine, called form E, after research. Form E has an X-ray powder diffraction pattern having diffraction peaks at 8.35,9.83, 10.38, 17.56, 17.74, 19.76, 23.42, 25.81, 26.23, and 27.41 degrees 2 θ (units: degrees, °, error ± 0.2 ℃).

In some embodiments, the crystalline form E has an X-ray powder diffraction pattern having diffraction peaks, in terms of 2 Θ, at 8.35,9.83, 10.38, 13.34, 17.56, 17.74, 19.76, 23.42, 25.26, 25.81, 26.23, 26.90, 27.17, 27.41, and 29.77 degrees.

In some embodiments, form E has an X-ray powder diffraction pattern having diffraction peaks at 8.35,9.83, 10.38, 13.34, 16.76, 17.56, 17.74, 18.01, 19.76, 20.87, 22.51, 22.98, 23.42, 25.26, 25.81, 26.23, 26.90, 27.17, 27.41, 28.97, 29.77, and 34.56 degrees 2 Θ.

In some embodiments, form E has an X-ray powder diffraction (XRPD) pattern as shown in figure 10.

The crystal form E also has the following characteristics that an endothermic peak is provided in a Differential Scanning Calorimetry (DSC) curve at 130-142 ℃. In some embodiments, form E has an endothermic peak at 133 ℃ to 138 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, form E has an endothermic peak in its Differential Scanning Calorimetry (DSC) curve with a peak top value of 135 ℃.

The thermogravimetric analysis curve (TGA) of the crystal form E has weight loss at 60-120 ℃, and the weight loss exceeds 15%.

In some embodiments, the thermogravimetric analysis curve of form E has a weight loss of 19.32% at 60 ℃ to 120 ℃. Form E is considered a solvate according to its TGA results. In some embodiments, the crystalline form E is a solvate of descemet's dimethyl sulfoxide with a molar ratio of descemet to dimethyl sulfoxide of 1.

A process for preparing the crystalline form E comprising: dissolving dexmedic in dimethyl sulfoxide, adding an anti-solvent such as water, ethanol, acetone, ethyl acetate or a combination thereof, crystallizing at 10-30 ℃, filtering, and drying to obtain a crystal form E. The volume ratio of the antisolvent to the dimethyl sulfoxide may be from 0.5 to 1, preferably from 2 to 1; the mass volume ratio of descales to dimethyl sulfoxide may be from 10mg to 11ml.

In some embodiments, a method of making the crystalline form E comprises: dissolving the desdox in dimethyl sulfoxide, and volatilizing at the temperature of 20-80 ℃ to remove the solvent to obtain a crystal form E; the mass-volume ratio of the descalestat to the dimethyl sulfoxide is 1mg.

In some embodiments, a method of making the crystalline form E, comprises: mixing the Dedostat with dimethyl sulfoxide and at least one of ethyl acetate, acetone, methyl isobutyl ketone, ethanol and 1, 4-dioxane, suspending and stirring at 20-80 ℃ for 24-48 hours, filtering and drying to obtain a crystal form E; the mass-volume ratio of the descalestat to the solvent is 5 mg.

The inventors have also developed a new form of dedospitabine, called form F, after research.

According to some embodiments of the invention, form F has an X-ray powder diffraction pattern having diffraction peaks at positions where 2 Θ (units: degrees, °, error ± 0.2 °) is 8.27,8.90,9.43, 16.47, 17.06, 18.93, 24.73 and 26.51 degrees.

According to some embodiments of the invention, form F, having an X-ray powder diffraction pattern with diffraction peaks at 8.27,8.90,9.43, 14.36, 15.47, 16.47, 17.06, 18.93, 21.73, 23.73, 24.73, 26.51, and 27.01 degrees 2 Θ.

In some embodiments, the crystalline form F has an X-ray powder diffraction pattern with diffraction peaks at 2 Θ at 8.27,8.90,9.43, 12.51, 13.28, 14.36, 15.47, 16.47, 17.06, 18.93, 20.64, 21.73, 21.85, 23.31, 23.73, 24.73, 26.51, 27.01, 28.37, 30.15, and 33.12 degrees.

In some embodiments, an X-ray powder diffraction (XRPD) pattern of form F is shown in figure 11.

The crystal form F also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has an endothermic peak within the range of 112-125 ℃. In some embodiments, the form F has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak with a peak top value of 120 ℃.

The crystal form F also has the following characteristics that the thermogravimetric analysis curve (TGA) of the crystal form F has weight loss between 60 ℃ and 130 ℃, and the weight loss exceeds 20 percent. In some embodiments, the thermogravimetric analysis curve (TGA) of form F has a weight loss of 22.28% between 60 ℃ and 130 ℃. Form F is considered a solvate according to its TGA results.

A process for preparing the crystalline form F comprising: dissolving the dexrazoxane in N-methylpyrrolidone or a mixed solvent of N-methylpyrrolidone and at least one of water, ethyl acetate and acetone, and then volatilizing at 20-80 ℃ to remove the solvent to obtain a crystal form F; the mass-to-volume ratio of the dedospitabine to the solvent used can be 1mg.

In some embodiments, a method of making the crystalline form F, comprises: mixing at least one of ethyl acetate and methyl tert-butyl ether and a mixed solvent of N-methyl pyrrolidone with the Dedostat, suspending and stirring for a period of time at 20-80 ℃, and filtering to obtain the crystal form F.

In some embodiments, a method of making the crystalline form F, comprises: dissolving the Dedostat in N-methylpyrrolidone, adding an anti-solvent ethanol, isopropyl ether or a combination thereof after dissolving, crystallizing at the temperature of 10-30 ℃, filtering and drying to obtain a crystal form F; the volume ratio of the antisolvent to the N-methylpyrrolidone is 0.5; the mass to volume ratio of descales to N-methylpyrrolidone may be 10mg.

A new form of Dedossier, form G, has an X-ray powder diffraction pattern having diffraction peaks at positions where 2 θ (in degrees, with a deviation of + -0.2 °) is 8.31,8.60,9.01, 10.24, 15.73, 17.21, 19.34 and 24.90 degrees.

In some embodiments, form G has an X-ray powder diffraction pattern with diffraction peaks at 8.31,8.60,9.01,9.60, 10.24, 15.73, 16.63, 17.21, 19.34, and 24.90 degrees 2 Θ.

In some embodiments, form G has a diffraction peak in its X-ray powder diffraction pattern at a position having a 2 Θ of 8.31,8.60,9.01,9.60, 10.24, 10.95, 11.69, 13.52, 15.73, 16.63, 16.72, 17.21, 17.62, 18.05, 19.34, 22.11, 24.90, 27.63, and 30.27 degrees.

In some embodiments, form G has an X-ray powder diffraction (XRPD) pattern as shown in figure 12.

A process for preparing the crystalline form G comprising: dissolving the Dedostat in a mixed solvent of N, N-dimethylacetamide and an organic solvent, and volatilizing at 40-80 ℃ to remove the solvent to obtain a crystal form G; the organic solvent is at least one of ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetonitrile, 1, 4-dioxane and methyl tert-butyl ether; the mass-volume ratio of the descales to the used mixed solvent can be 1mg.

A new form of descaler, form H, having X-ray powder diffraction pattern with diffraction peaks at positions of 4.88,7.63,8.21,8.37,8.72,9.21, 10.73, 12.09, 12.55, 14.57, 14.76, 15.82, 16.26, 17.49, 18.50, 19.38, 22.77, 23.09, 23.65, 26.83, 27.56 and 28.49 degrees 2theta (units: degrees, °, error ± 0.2 °).

In some embodiments, form H has an X-ray powder diffraction pattern with diffraction peaks at positions 4.88,7.63,8.21,8.37,8.72,9.21,9.65, 10.24, 10.73, 12.09, 12.55, 14.57, 14.76, 15.82, 16.26, 16.71, 17.49, 18.50, 19.38, 22.77, 23.09, 23.65, 24.04, 24.36, 24.89, 25.35, 26.54, 26.83, 27.56, and 28.49 degrees 2 Θ.

In some embodiments, form H has an X-ray powder diffraction pattern with diffraction peaks at 4.88,7.63,8.21,8.37,8.72,9.21,9.65, 10.24, 10.73, 11.77, 12.09, 12.55, 13.53, 14.57, 14.76, 15.82, 16.26, 16.71, 17.49, 18.50, 18.95, 19.38, 19.75, 20.66, 21.26, 22.01, 22.41, 22.77, 23.09, 23.65, 24.04, 24.36, 24.89, 25.35, 26.54, 26.83, 27.56, 28.49, 29.37, and 31.69 degrees 2 Θ.

In some embodiments, form H has an X-ray powder diffraction (XRPD) pattern as shown in figure 13.

A process for preparing the crystalline form H comprising: dissolving the dexrazoxane in a mixed solvent of N, N-dimethylacetamide and methyl isobutyl ketone, or dissolving the dexrazoxane in a mixed solvent of N, N-dimethylacetamide and dimethyl carbonate, and then volatilizing the solvent at 40-80 ℃ to obtain a crystal form H; the mass volume ratio of the desdoxetas to the mixed solvent can be 1mg to 501mg. The volume ratio of the N, N-dimethylacetamide to the dimethyl carbonate or methyl isobutyl ketone can be 1.

In another aspect, the invention also provides a crystalline form of dexrazoxane, designated form I.

The crystal form I has diffraction peaks at positions with 2theta (unit: degree, error +/-0.2 ℃) of 8.15 degrees, 8.51 degrees, 8.78 degrees, 10.26 degrees, 16.45 degrees, 18.03 degrees, 22.56 degrees, 24.52 degrees and 24.69 degrees in an X-ray powder diffraction pattern.

In some embodiments, form I, having an X-ray powder diffraction pattern with diffraction peaks at 8.15,8.51,8.78, 10.26, 11.19, 16.45, 17.07, 17.50, 18.03, 19.32, 22.56, 24.52, 24.69, and 25.05 degrees 2 Θ.

In some embodiments, form I, having an X-ray powder diffraction pattern with diffraction peaks at 8.15,8.51,8.78,9.63, 10.26, 11.19, 12.44, 16.45, 17.07, 17.50, 18.03, 18.92, 19.32, 20.55, 20.83, 22.56, 23.71, 24.52, 24.69, 25.05, 25.58, 27.87, 28.38, 29.00, 29.81, 32.96, 33.28, and 36.59 degrees 2 Θ.

In some embodiments, an X-ray powder diffraction (XRPD) pattern of form I is shown in figure 14.

A process for preparing the form I comprising: dissolving the Dedostat in a mixed solvent of ethylene glycol monomethyl ether and ethyl acetate or a mixed solvent of ethylene glycol monomethyl ether and isopropyl ether, and then volatilizing at 40-80 ℃ to remove the solvent to obtain a crystal form I; the mass-volume ratio of the descales to the mixed solvent can be 1mg.

According to the characteristics and performance research of the various crystal forms, the crystal form A and the crystal form D-1 have better stability, are favorable for operation in storage, transfer and production processes, and can be prepared into a medicinal composition together with a pharmaceutically acceptable carrier; and other crystal forms have more or less properties which are not suitable for preparing a pharmaceutical preparation, such as relatively low stability, or solvate, higher insecurity and the like, or poor solubility, unfavorable dissolution of the preparation and the like.

The crystal form A and the crystal form D-1 are also powder with good appearance and fluidity, have relatively good performances in the aspects of dissolution rate, fluidity and the like, are favorable for operation in storage, transfer and production processes, and are suitable for being prepared into medicinal compositions with pharmaceutically acceptable carriers.

In another aspect, the invention also provides a composition.

A composition, comprising: at least one selected from the group consisting of the aforementioned form A, form B, form C, form D-1, form E, form F, form G, form H and form I, and a pharmaceutically acceptable excipient.

In some embodiments, a composition comprises form a of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable adjuvant; at least one selected from the group consisting of the aforementioned form B, form C, form D-1, form E, form F, form G, form H and form I may also be included. In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable excipient; the aforementioned form D-1 may also be included.

In some embodiments, a composition comprises form D-1 as previously described and a pharmaceutically acceptable excipient. In some embodiments, a composition comprising the aforementioned crystalline form D-1 and a pharmaceutically acceptable excipient; at least one of the crystal form A, the crystal form B, the crystal form C, the crystal form D, the crystal form E, the crystal form F, the crystal form G, the crystal form H and the crystal form I and pharmaceutically acceptable auxiliary materials can also be included.

In some embodiments, the crystalline form is at least 80% of descemet, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 85% of desserts, by mass, in the composition. In some embodiments, the crystalline form is at least 90% of desserts, by mass, in the composition. In some embodiments, the crystalline form is at least 95% of dolichthazine, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 97% of desserts, by mass, in the composition. In some embodiments, the crystalline form is at least 99% of dolostone by mass in the composition.

In some embodiments, the crystalline form is at least 10% of dedospitabine, calculated as mass. In some embodiments, the crystalline form is at least 5% of descemet, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 1% of descemet, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 0.5% by mass of the composition. In some embodiments, the crystalline form is at least 5% to 10% by mass of the composition.

In some embodiments, the crystalline form is no more than 10% by mass of the composition. In some embodiments, the crystalline form is no more than 6% by mass of the composition. In some embodiments, the crystalline form is no more than 5% by mass of the composition, calculated as mass. In some embodiments, the crystalline form is no more than 3% by mass of the composition. In some embodiments, the crystalline form is not more than 1% by mass of the composition. In some embodiments, the crystalline form is not more than 0.5% by mass of the composition.

In some embodiments, the crystalline form is at least 0.05% to 95%,0.1% to 95%,1% to 95%,5% to 95%, or 1% to 50% by mass of the total mass of the composition, calculated as a mass ratio.

In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable excipient; the crystal form A is at least 5-10% of the Dedossier calculated according to the mass ratio. In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable excipient; the crystal form A accounts for at least 0.5-5% of the total weight of the composition according to the mass ratio. In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable excipient; the crystal form A is at least 80 percent of the Dedossier according to the mass ratio. In some embodiments, a composition comprising form a of the foregoing and a pharmaceutically acceptable adjuvant; the crystal form A is at least 90%, or at least 95%, or at least 99% of the total weight of the composition calculated according to the mass ratio.

In some embodiments, a composition comprising the aforementioned crystalline form D-1 and a pharmaceutically acceptable excipient; according to the mass ratio, the crystal form D-1 is at least 5% -10% of the dolostone. In some embodiments, a composition comprising the aforementioned crystalline form D-1 and a pharmaceutically acceptable excipient; according to the mass ratio, the crystal form D-1 accounts for at least 0.5-5% of the total weight of the composition. In some embodiments, a composition comprising the aforementioned crystalline form D-1 and a pharmaceutically acceptable excipient; the crystal form D-1 is at least 80 percent of the Dedossier according to the mass ratio. In some embodiments, a composition comprising the aforementioned crystalline form D-1 and a pharmaceutically acceptable excipient; the crystal form D-1 accounts for at least 90 percent, or at least 95 percent, or at least 99 percent of the total weight of the composition according to the mass ratio.

In some embodiments, the composition, including the aforementioned form a or form D-1 and pharmaceutically acceptable excipients, may further include form a.

The pharmaceutically acceptable auxiliary materials comprise a diluent, a disintegrating agent, an adhesive, a lubricant or the like.

The various crystal forms can be used for preparing a medicine for treating anemia caused by chronic kidney disease.

The composition can be used for preparing a medicine for treating anemia caused by Chronic Kidney Disease (CKD).

Drawings

Figure 1 shows an X-ray powder diffraction pattern (XRPD) of form a;

FIG. 2 shows a Differential Scanning Calorimetry (DSC) curve of form A;

figure 3 shows a thermogravimetric analysis plot (TGA) of form a.

Figure 4 shows an X-ray powder diffraction pattern (XRPD) of form B;

figure 5 shows an X-ray powder diffraction pattern (XRPD) of form C.

Figure 6 shows an X-ray powder diffraction pattern (XRPD) of form D.

FIG. 7 shows an X-ray powder diffraction pattern (XRPD) of form D-1;

FIG. 8 shows a Differential Scanning Calorimetry (DSC) curve of form D-1;

figure 9 shows a thermogravimetric analysis plot (TGA) of form D-1.

Figure 10 shows an X-ray powder diffraction pattern (XRPD) of form E;

figure 11 shows an X-ray powder diffraction pattern (XRPD) of form F;

figure 12 shows an X-ray powder diffraction pattern (XRPD) of form G.

Figure 13 shows an X-ray powder diffraction pattern (XRPD) of form H.

Figure 14 shows an X-ray powder diffraction pattern (XRPD) of form I.

Fig. 15 shows a DVS plot of form α.

Fig. 16 shows a DVS plot for form a.

Figure 17 shows a DVS plot for form D-1.

Figure 18 shows the concentration of each form in hydrochloric acid buffer as a function of time for example 24.

In the above drawings, 2Theta represents 2Theta, temperature (deg.C) represents Temperature (deg.C), heat Flow (W/g) represents Heat Flow (Watt/gram), J/g represents Joule/gram, weight represents Weight, target RH represents Target relative humidity, change in Mass represents Change, and Cycle 1 represents Cycle 1.

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 the methods described herein.

In the present invention, MG or MG represents MG, and ML or ML represents ML; nm represents nanometers; rpm represents revolutions per minute; in relation to time, min represents minutes, H or H represents hours, d represents days; RH means relative humidity; SDS represents sodium dodecyl sulfate; DMSO denotes dimethyl sulfoxide.

In the present invention, unless otherwise specified, room temperature refers to ambient temperature, at 15-40 ℃, or 20-30 ℃, or 22-28 ℃.

Parameters of the instrument

All analyses below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction (XRPD) study

Collection on a PANALYTIC EMPyrean X-ray diffractometer equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holderX-ray powder diffraction (XRPD) pattern. The radiation source used is (Cu, K alpha, K alpha 1)

：1.540598；Kα2

:1.544426; k α 2/K α 1 intensity ratio: 0.50 Voltage is set at 45KV, current is set at 40ma, beam divergence of X-ray, i.e., the effective size of X-ray confinement on the sample, is 6.6mm, and a theta-theta continuous scanning mode is employed to obtain an effective 2theta range of 3 deg. to 60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample holder 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 holder. The sample was scanned in 0.0167 ° steps over a range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.

Differential Scanning Calorimetry (DSC)

DSC measurements were performed in a TA instruments model Q2000 using a sealed tray 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 30 ℃ and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak is plotted downward, and the data is analyzed and displayed using TA Universal Analysis.

Thermogravimetric analysis (TGA)

TGA data were collected on TA Instruments Q500. The temperature of the instrument was calibrated using certified nickel. Typically, 8-12mg of sample was loaded onto a pre-weighed platinum crucible and heated from 30 ℃ to 300 ℃ at 10 ℃/min. A60 mL/min nitrogen purge was maintained over the sample. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents Weight loss in percentage (Weight (%)).

EXAMPLE 1 preparation of form A

30.0mg of doxetas and 1.0ml of water are respectively added into a 5ml EP tube (centrifuge tube), magnetically stirred at 50.0 ℃ and 200rpm, stirred and suspended for 24 hours, then filtered and dried at room temperature to obtain about 23.3mg of a product, which is detected as crystal form A, and the results of X-ray powder diffraction, DSC and TGA are shown in figure 1-figure 3.

Example 2 preparation of form a

30.0mg of dexmedic and 1.0ml of ethanol are respectively added into a 5ml EP tube, magnetic stirring is carried out at 50.0 ℃,200rpm is carried out, stirring and suspending are carried out for 24 hours, then filtration and drying at room temperature are carried out, and about 23.3mg of product is obtained, and the crystal form A is detected.

EXAMPLE 3 preparation of form A

Respectively adding 30.0mg of delta and 0.5ml of ethylene glycol monomethyl ether into a 5ml EP tube, magnetically stirring at 70.0 ℃, and completely dissolving the solid to form a solution at 200 rpm; dropwise adding 2.5ml of ethanol at room temperature, separating out solid, stirring for 24 hours after the solid is added, filtering to obtain about 24.7mg of solid, and detecting to obtain the crystal form A.

Example 4 preparation of form a

Adding 30mg of desdoxetat and 1mL of ethylene glycol dimethyl ether into a 5mL EP tube, magnetically stirring at 50.0 ℃, completely dissolving the solid at 200rpm, slowly volatilizing after dissolving, separating out the solid, filtering to obtain about 22.7mg of a product, and detecting to obtain a crystal form A.

EXAMPLE 5 preparation of form A

Adding 30mg of desdoxetat and 2mL of isobutanol into a 5mL EP tube, magnetically stirring at 75.0 ℃, completely dissolving the solid at 200rpm, slowly cooling to 0 ℃ after dissolving, separating out the solid, filtering to obtain about 23.8mg of a product, and detecting to obtain the crystal form A.

EXAMPLE 6 preparation of form B

30.0mg of dexsitol and 1.0mL of 1, 4-dioxane were added to a 5mL EP tube, suspended for 24h at about 50.0 deg.C and 200rpm with magnetic stirring, and then filtered to give about 21.5mg of product; x-ray powder diffraction, DSC and TGA are detected, and the result is shown in figure 4 and is the crystal form B.

EXAMPLE 7 preparation of form B

30mg of Dedosstane and 2mL1, 4-dioxane are added into a 5ml EP tube, magnetic stirring is carried out at 75.0 ℃ and 200rpm, the solid is completely dissolved, the temperature is slowly reduced to 0 ℃ after the solid is dissolved out, the solid is separated out, and the product with the concentration of about 22.6mg is obtained by filtration and detected to be crystal form B.

EXAMPLE 8 preparation of form C

30mg of Dedosstat and 0.5mL of N, N-dimethylformamide are added into a 5ml EP tube, magnetic stirring is carried out at 50.0 ℃ and 200rpm, the solid is completely dissolved, the solution is slowly volatilized after being clear, the solid is separated out and filtered, about 22.4mg of product is obtained, and the crystal form C is detected, wherein XRPD of the crystal form C is shown in figure 5.

Example 9 preparation of form C

40mg of doxetastat, 0.1mL of N, N-dimethylformamide and 1.5mL of isopropyl acetate are added into a 5mL EP tube, and the mixture is magnetically stirred and suspended for 24 hours at 50.0 ℃ and 200rpm, filtered to obtain about 31.6mg of a product, and detected and confirmed to be a crystal form C.

EXAMPLE 10 preparation of form C

30mg of Dedostat and 0.4mL of N, N-dimethylformamide are added into a 5mL EP tube, magnetic stirring is carried out at 50.0 ℃ and 200rpm, the solid is completely dissolved, 3mL of methyl tert-butyl ether (the dropwise adding mode can be positive or reverse) is slowly dropwise added after the solid is completely dissolved, the solid is separated out, and the product of 23.7mg is obtained by filtration and detected to be the crystal form C.

EXAMPLE 11 preparation of form D

30mg of Dedostat and 2mL of dimethyl carbonate are added into a 5mL EP tube, magnetic stirring is carried out at 75.0 ℃ and 200rpm, the solid is completely dissolved, the temperature is reduced to 0 ℃ after the solid is dissolved, the solid is separated out, and the filtration is carried out to obtain about 23.2mg of a product which is detected to be crystal form D, wherein XRPD of the crystal form D is shown in figure 6.

EXAMPLE 12 preparation of form D-1

20mg of the sample of form D of desdoxat was added to a 5ml EP tube and dried under vacuum at 50.0 ℃ for 12h to give about 19.5mg of the product, which was examined for X-ray powder diffraction, DSC, TGA, and the results are shown in FIG. 7-FIG. 9 as form D-1.

Example 13 preparation of form E

Adding 30mg of Dedostilde and 1mL of dimethyl sulfoxide into a 5mL EP tube, magnetically stirring at 50.0 ℃ and 200rpm, completely dissolving the solid, slowly volatilizing after dissolving, separating out the solid, filtering to obtain about 23.5mg of a product, and detecting XRPD, DSC and TGA of the product; see fig. 10, form E.

Example 14 preparation of form E

40mg of Dedostat, 0.1mL of dimethyl sulfoxide and 1.5mL of ethyl acetate are added into a 5mL EP tube, and the mixture is magnetically stirred and suspended for 24 hours at 50.0 ℃ and 200rpm, and then filtered to obtain about 33.5mg of a product which is detected to be crystal form E.

Example 15 preparation of form E

And adding 30mg of Dedosstat and 0.5mL of dimethyl sulfoxide into a 5mL EP tube, magnetically stirring at 50.0 ℃ and 200rpm to completely dissolve the solid, slowly dropwise adding 2.5mL of water after the solid is completely dissolved, separating out the solid, and filtering to obtain about 24.6mg of a product, namely the crystal form E.

EXAMPLE 16 preparation of form F

Adding 30mg of delta and 0.5mL of N-methylpyrrolidone into a 5mL EP tube, magnetically stirring at 50.0 ℃ and 200rpm to completely dissolve the solid, slowly volatilizing the solvent after dissolving, separating out the solid, filtering to obtain about 24.3mg of a product, and detecting the XRPD, DSC and TGA of the product; see fig. 11, form F.

Example 17 preparation of form F

40mg of doxetastat, 0.1mL of N-methylpyrrolidone and 1.5mL of ethyl acetate are added into a 5mL EP tube, and the mixture is suspended for 24 hours under the conditions of 50.0 ℃ and 200rpm by magnetic stirring and filtered to obtain about 23.1mg of a product which is detected to be a crystal form F.

Example 18 preparation of form F

Adding 30mg of Dedostilde and 0.5mL of N-methylpyrrolidone into a 5mL EP tube, magnetically stirring at 50.0 ℃ and 200rpm, completely dissolving the solid, slowly dripping 2.5mL of ethanol after the solid is dissolved clearly, separating out the solid, filtering to obtain about 22.7mg of a product, and detecting to obtain a crystal form F.

EXAMPLE 19 preparation of form G

20mg of Dedosstat, 0.5mL of N, N-dimethylacetamide and 3mL of ethyl acetate are added into a 5mL EP tube, magnetic stirring is carried out at 50.0 ℃ and 200rpm, the solid is completely dissolved, the solvent is slowly volatilized after the solid is dissolved clearly, the solid is separated out, and the product of 17.3mg is obtained by filtering, wherein XRPD of the product is shown in figure 12 and is crystal form G.

EXAMPLE 20 preparation of form H

20mg of Dedosstat, 0.5mL of N, N-dimethylacetamide and 3mL of methyl isobutyl ketone are added into a 5mL EP tube, magnetic stirring is carried out at 50.0 ℃ and 200rpm, the solid is completely dissolved, the solvent is slowly volatilized after the solid is dissolved clearly, the solid is separated out and filtered, and 16.7mg of a product is obtained, wherein XRPD of the product is detected as shown in figure 13 and is in a crystal form H.

EXAMPLE 21 preparation of form I

30mg of Dedosstat, 0.5mL of ethylene glycol monomethyl ether and 2.5mL of ethyl acetate are added into a 5mL EP tube, magnetic stirring is carried out at 50.0 ℃ and 200rpm, the solid is completely dissolved, the solvent is slowly volatilized after the solid is completely dissolved, the solid is separated out and filtered, and about 23.4mg of a product is obtained, and the XRPD of the product is detected to be shown in figure 14 and is in a crystal form I.

Example 22 stability test

1) Pre-experiment: the obtained crystal forms A, B, C, D, E, F, G, H and I of the Dedossier are placed in a vacuum drying oven at 50.0 ℃ for drying for 12 hours, then a sample is taken for detecting XRPD, the condition of the crystal forms is confirmed, and the results are shown in the following table 1.

Table 1: stability study at 50.0 ℃ vacuum drying

Crystal form of raw material	Treatment method	Crystal form of product
			Crystal form A	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form A
Crystal form B	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form B
			Crystal form C	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form alpha
Crystal form D	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form D-1
			Crystal form E	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form E
Crystal form F	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form F
			Crystal form G	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form alpha
Crystal form H	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form alpha
			Crystal form I	Vacuum drying at 50.0 deg.C for 12 hr	Crystal form alpha

According to the results, after vacuum drying for 12 hours at 50.0 ℃, the crystal forms A, B, E and F are not changed, the crystal forms C, G, H and I are transformed to the crystal form alpha, and the crystal form D is transformed to the crystal form D-1, so that the crystal forms A, B, E and F can be kept stable after drying for 12 hours at 50 ℃, and the crystal form D-1 also has relatively high stability.

2) According to the guiding principle of the stability test of the bulk drugs, the sample is subjected to influence factor tests including a high temperature test, a high humidity test and a strong light irradiation test, the stability conditions of each crystal form under different conditions are investigated, and the specific test conditions are as follows:

light test (light UV + VIS): respectively taking a proper amount of samples, spreading the samples into a weighing bottle, opening the weighing bottle, placing the bottles in a constant temperature and humidity box (25 ℃, RH 60% +/-5%) with visible light of 4500Lux +/-500 Lux (VIS) and ultraviolet light of 1.7W X h/m & lt 2 & gt (UV), then respectively taking about 10mg of the samples in 0 and 15 days, and testing the crystal form condition by X-ray powder diffraction (XRPD);

high humidity test (high humidity 25 ℃ +92.5% rh): respectively sampling a proper amount of samples, flatly placing the samples in a weighing bottle, opening the bottle, placing the bottle in a constant temperature and humidity box with the temperature of 25 ℃ and RH being 92.5 +/-5 percent, then respectively sampling about 10mg of samples in 0 and 15 days, and testing the crystal form condition by adopting X-ray powder diffraction (XRPD);

high temperature high humidity test (high temperature 60 ℃ +75% rh): a proper amount of samples are respectively taken, laid in a weighing bottle, opened, placed in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5 percent, then samples are respectively taken for about 10mg in 0 and 15 days, and the crystal form condition is tested by adopting X-ray powder diffraction (XRPD). The results of the measurements for each sample are shown in Table 2.

Table 2: results of stability experiments

From the results, it can be seen that: the crystal form A and the crystal form alpha can keep unchanged under the conditions of high temperature, high humidity and illumination, and the crystal form A and the crystal form alpha are stable under the conditions of influencing factors.

3) Respectively stirring and suspending the crystal form A, the crystal form D-1 and the crystal form alpha in water at 37 ℃ for 1 day, filtering, drying, and testing the crystal forms of the obtained solid, wherein the results are shown in the following table 3.

Table 3: stability study of Crystal forms in Water

Crystal form of raw material	Temperature of	Time of stirring	Crystal form of product
				Crystal form alpha	37℃	1d	Crystal form A
Crystal form A	37℃	1d	Crystal form A
				Crystal form alpha + crystal form A	37℃	1d	Crystal form A
Crystal form A + crystal form D-1	37℃	1d	Crystal form A
				Crystal form alpha + crystal form D-1	37℃	1d	Crystal form A
Crystal form D-1	37℃	1d	Crystal form A

From the results, the crystal form A is transformed after the crystal form alpha and the crystal form D-1 of the dedospitabine are suspended in water at 37 ℃ for a certain time, the crystal form A is not changed after suspended in water at 37 ℃ for a certain time, and the crystal form A is obtained after the crystal form A, the crystal form D-1 and the crystal form alpha are combined in pairs respectively and suspended in water at 37 ℃ for a certain time, which shows that the crystal form A is more stable than the crystal form D-1 and the crystal form alpha. The result is combined, the crystal form A is considered to be relatively more stable, and the relatively better stability is beneficial to reservoir formation and transfer in the preparation process, and crystal form control, impurity control and the like in preparation.

Example 23 DVS dynamic moisture sorption testing

With the change of relative humidity (0% -95.0% -0%) under the condition of 25.0 ℃, starting from 0% relative humidity, reaching 95% relative humidity in the step change of 10% relative humidity, and then reaching 0% relative humidity in the step change of 10% relative humidity; when the absolute value of the change dm/dt in the weight of the sample per unit time under a certain relative humidity condition is less than 0.1%, the sample is considered to reach the equilibrium, and then the next relative humidity is entered. And detecting the variation of hygroscopicity of the samples of each crystal form of Desidustat under the circulation condition of (0% -95.0% -0%) relative humidity to obtain the DVS diagram of each crystal form.

DVS results for form α, form a, and form D-1 of dolostone are shown in fig. 15-17. The hygroscopicity of the crystal form alpha is increased sharply after the humidity of a DVS curve is more than 80%, and the hygroscopicity and the weight gain reach the maximum when the humidity is 95%, and are about 2.72%. The hygroscopicity of the crystal form A is increased rapidly after the humidity of a DVS curve is more than 80%, and when the humidity is 95%, the hygroscopicity increase is only 0.78%, which indicates that the crystal form A has lower hygroscopicity. The hygroscopicity of the crystal form D-1 is slowly increased after the humidity of a DVS curve is more than 50%, and the hygroscopicity increasing weight is only 0.32% when the humidity is 95%, which indicates that the crystal form D-1 also has lower hygroscopicity. The relatively low hygroscopicity of form a and form D-1 is relatively more advantageous for the storage, transfer and/or preparation of pharmaceutical products.

Example 24 measurement of Change in concentration in crystalline hydrochloric acid buffer

Dissolving 2mg of Dedoxat (crystal form alpha) in 20mL of mixed solution of DMSO and a pH =1.2 hydrochloric acid buffer solution (volume ratio is 1: 293nm.

The dilution method of the dilution is as follows: 1.5mL of a 0.1mg/mL solution and a mixed solution of 1.5mL of DMSO and a pH =1.2 hydrochloric acid buffer solution (volume ratio 1).

Scanning in the wavelength range of 260-400nm, recording the ultraviolet absorption peak intensity values of different concentrations, and drawing an absorption intensity-concentration standard curve (the characteristic peak corresponds to the ultraviolet wavelength: 293 nm).

Mixing the crystal form alpha, the crystal form A and the crystal form D-1 of the desdox with a hydrochloric acid buffer solution of 50mlpH =1.2 at 37 ℃, continuously stirring, sampling at 5min, 10min, 20min, 30min, 45min, 1h, 2h, 5h, 8h, 10h and 24h, filtering, mixing 1.5mL and 1.5mlDMSO solvent, scanning at a characteristic peak wavelength of 293nm to obtain an absorption intensity value, further calculating the concentration of each crystal form of the desdox in the hydrochloric acid buffer solution of pH =1.2 at 37 ℃, and drawing a curve of the concentration of each crystal form along with the change of time, wherein the API refers to the desdox crystal form alpha in the figure 18.

As can be seen from fig. 18, in hydrochloric acid buffer pH =1.2, form a and form a have relatively high concentrations (i.e. better solubility) within 2h-5h, and form D-1 is relatively low (i.e. poorer solubility); over time, after 8h to 10h, the concentration of form a reached a relatively high value and tended to be in equilibrium, while form a and form D-1 were relatively low (i.e., poor solubility) and tended to decrease (i.e., further decrease). From the time-varying concentration results, it can be known that the crystal form a has a high and stable dissolution characteristic, and is relatively more favorable for preparing a pharmaceutical preparation and dissolving the pharmaceutical preparation.

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 (10)

1. A crystalline form of dolostone comprising: form a having an X-ray powder diffraction pattern with diffraction peaks at 10.31, 11.25, 14.74, 17.53, 19.02, 21.28, 21.70, 22.57, 27.05, and 28.23 degrees 2 Θ.

2. The crystalline form of claim 1, wherein the form a has an X-ray powder diffraction pattern having diffraction peaks at 10.31, 11.25, 14.74, 17.53, 19.02, 19.75, 21.28, 21.70, 22.57, 24.53, 27.05, 28.23, 34.56, and 38.54 degrees 2 Θ, or the form a has an X-ray powder diffraction pattern having diffraction peaks at 10.31, 11.25, 14.06, 14.74, 17.53, 18.21, 19.02, 19.75, 21.28, 21.70, 22.57, 23.27, 24.53, 25.83, 27.05, 28.23, 29.66, 30.15, 34.56, and 38.54 degrees 2 Θ.

3. The crystalline form of claim 1, wherein form a has a differential scanning calorimetry curve with an endothermic peak in the range of 208 ℃ to 218 ℃, and/or a thermogravimetric analysis curve without weight loss below 200 ℃.

4. The crystalline form according to any one of claims 1-3, wherein, the X-ray powder diffraction pattern of the crystal form A is shown as attached figure 1.

5. A process for preparing the crystalline form of any one of claims 1 to 4,

the method comprises the following steps: dissolving the Dedoxetastat in a crystallization solvent, crystallizing at-10-25 ℃, filtering, and removing the solvent to obtain a crystal form A; the crystallization solvent is at least one of isobutanol, ethyl acetate and acetonitrile;

or comprises the following steps: dissolving the Dedoxetastat in a good solvent, mixing the obtained solution with an anti-solvent, crystallizing at the temperature of-5-50 ℃, filtering, and removing the solvent to obtain a crystal form A; the good solvent is ethylene glycol dimethyl ether, N, N-dimethylacetamide or a combination thereof; the anti-solvent is ethanol, isopropanol or a combination thereof;

or comprises the following steps: mixing the descales with a solvent, suspending and stirring at 20-80 ℃ for 20 hours or more, filtering, and removing the solvent to obtain a crystal form A; the solvent is at least one of water, methanol, ethanol, isopropanol, n-butanol, acetone, butanone, methyl isobutyl ketone, ethyl formate, butyl formate, ethyl acetate, isopropyl acetate, acetonitrile, isopropyl ether and methyl tert-butyl ether, and the mass volume ratio of the Dedostat to the solvent is 1 mg-100mg.

6. The process according to claim 5, wherein the mass to volume ratio of dedustite to crystallization solvent is from 10mg to 1100mg; or alternatively

The mass volume ratio of the desdoxat to the good solvent is 5 mg.

7. The process according to claim 5, wherein the Dedoxat is dissolved in the crystallization solvent at 20-80 ℃.

8. A composition comprising the crystalline form a of any one of claims 1-4 and 5-6 and a pharmaceutically acceptable carrier; the crystal form A is at least 90% of the descemet, or the crystal form A is at least 0.5% of the descemet, or the crystal form A is not more than 10% of the descemet according to the mass ratio.

9. The composition according to claim 8, wherein the form A is at least 0.05-95% of the total mass of the composition by mass ratio.

10. The composition according to any one of claims 8 to 9, optionally comprising form D-1, wherein form D-1 does not exceed 10% by mass of the dedocistat; the X-ray powder diffraction pattern of the crystal form D-1 has diffraction peaks with 2theta of 10.17, 11.12, 14.61, 17.42, 18.89, 21.15, 22.44, 24.40, 26.91 and 28.10 degrees; or form D-1 has an X-ray powder diffraction pattern having diffraction peaks at 10.17, 11.12, 14.61, 17.42, 18.89, 21.15, 21.57, 22.44, 24.40, 26.91, 27.43, 28.10, 29.53, 30.01, 34.43, and 38.41 degrees 2 Θ.

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