CN115872938A - Novel citrate crystal form of diaminopyrimidine compound and preparation method thereof - Google Patents
Novel citrate crystal form of diaminopyrimidine compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a novel citrate crystal form of a diaminopyrimidine compound and a preparation method thereof, and particularly discloses a citrate crystal form 13 of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form 13 has characteristic diffraction peaks at the following 2 theta angles: 7.2 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees and 14.6 degrees +/-0.2 degrees, and the crystal form 13 has better solubility compared with the crystal form in the prior art.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a novel citrate crystal form of a diaminopyrimidine compound and a preparation method thereof.
Background
From 5% to 10% of adults worldwide suffer from chronic cough. Some of these patients are Refractory Chronic Cough (RCC) and chronic cough of unknown cause (UCC), and are more sensitive to various causes that do not normally cause cough in healthy subjects. Currently, the drug options for these patients are extremely limited. P2X receptors are extracellular ligand-gated cation channels, and when P2X receptors bind to extracellular adenosine triphosphate, P2X channels open, allowing cations such as sodium and potassium to pass through, which in turn causes a series of physiological or pathological phenomena. The P2X3 receptor is a subtype of the P2X receptor that is generally believed to mediate vagal C and a δ fiber activation, the core of inducing cough and sensitization. Therefore, the P2X3 receptor is inhibited, and the cough symptom can be effectively relieved. 5- (2,4-diamino-pyrimidin-5-yloxy) -4-isopropyl-2-methoxy-benzenesulfonamide is an oral, selective P2X3 receptor antagonist having the following structural formula:
formula (I) selectively binds to P2X3 receptors, reducing the extent to which P2X3 receptors are activated and reducing the extent to which they mediate activation of C and A delta fibers of the vagus nerve. Therefore, formula (I) has certain therapeutic potential in the treatment of refractory chronic cough and chronic cough of unknown cause.
Patent CN1930135B discloses a free base of formula (I) and a preparation method thereof for the first time. The patent CN110087654a discloses the crystalline forms of citrate, namely citrate form a and citrate form B, but the solubility in water is still only 6 mg/ml although it is improved to some extent compared with the free base. Patent crystal form WO2019209607A1 discloses a method for the preparation of free base, and the methanol solvate, isopropanol solvate and methanol-water co-solvate of citrate, but the solvates have problems of residual solvent control during pharmaceutical use and thus are more prone to develop hydrates or anhydrous crystal forms.
Polymorphs of the same drug may change their physicochemical properties, such as solubility, which in turn may affect the effect of the drug in the human body. Therefore, there is a need to perform comprehensive and systematic crystal form screening on formula (I), develop a crystal form with better solubility and stability, and provide more and better choices for the subsequent development of drugs.
Disclosure of Invention
The compound shown in the formula (I) is a compound which is difficult to dissolve in water, and related researches such as salt form and crystal form are carried out on the compound in the prior art in order to improve the solubility of the compound, but the inventor finds that the solubility of the crystal form in the prior art is still low, and the problem of solvent residue exists.
In a first aspect of the invention, the invention provides a crystalline form 13 of the citrate salt of a compound of formula (I). According to an embodiment of the present invention, the form 13 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees and 14.6 degrees +/-0.2 degrees,
the solubility of form 13 according to the examples of the present invention is significantly higher than other forms in the prior art.
According to an embodiment of the present invention, the above form 13 may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the form 13 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees and 20.4 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the form 13 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees and 25.5 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the crystalline form 13 has an X-ray powder diffraction pattern substantially as shown in figure 1.
According to the embodiment of the invention, the crystal form 13 is a hydrate, and the moisture content is 5.0-7.0%. For example, the moisture content is 5.0%,5.1%,5.2%,5.3%,5.4%,5.5%,5.6%,5.7%,5.8%,5.9%,6.0%,6.1%,6.2%,6.3%,6.4%,6.5%,6.6%,6.7%,6.8%,6.9%.
According to an embodiment of the invention, the crystalline form 13 is a dihydrate.
According to the embodiment of the invention, the differential thermal analysis DSC curve of the crystal form 13 contains 1 endothermic peak at the position of 89 +/-3 ℃.
According to the embodiment of the invention, a differential thermal analysis DSC curve of the crystal form 13 is shown in figure 7.
TGA profile the TGA profile of the crystalline form 13 by thermogravimetric analysis according to an embodiment of the present invention is shown in figure 6.
In yet another aspect of the present invention, a method of preparing form 13 of citrate salt is also presented. According to an embodiment of the invention, the method comprises: 1) Suspending and stirring a compound shown in the formula (I) and a citric acid aqueous solution in an alcohol solvent for 1-5 hours, separating and drying to obtain a solid, and 2) performing gas-solid diffusion on the solid in the pure water solvent atmosphere, wherein the gas-solid diffusion is performed at the temperature of 20-30 ℃ for 1-10 days to obtain a citrate crystal form 13.
In a further aspect of the present invention, there is also provided crystalline form 18 of the citrate salt of the compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form 18 has characteristic diffraction peaks at the following 2 Θ angles: 8.5 degrees +/-0.2 degrees, 16.1 degrees +/-0.2 degrees and 22.6 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the above-mentioned crystalline form 18 may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form 18 has characteristic diffraction peaks at the following 2 Θ angles: 8.5 degrees +/-0.2 degrees, 14.8 degrees +/-0.2 degrees, 16.1 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees and 22.6 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the crystalline form 18 has an X-ray powder diffraction pattern substantially as shown in figure 2.
According to the embodiment of the invention, the DSC curve of the crystal form 18 contains 1 endothermic peak at the position of 95 +/-3 ℃.
A differential thermal analysis DSC curve of form 18 according to an embodiment of the present invention is shown in figure 10.
According to an embodiment of the present invention, the crystalline form 18 has a thermogravimetric analysis TGA profile with a weight loss of 3.89% at 100 ℃ ± 3 ℃.
A thermogravimetric analysis, TGA, curve of the crystalline form 18 according to an embodiment of the present invention is shown in figure 9.
In yet another aspect of the present invention, a method of preparing crystalline form 18 of citrate is also presented. According to an embodiment of the invention, the method comprises: 1) Dissolving citrate of the compound shown in the formula (I) in a nitrogen-containing solvent to obtain a dissolved product, and 2) dropwise adding an ester solvent into the dissolved product obtained in the step 1) or adding the dissolved product obtained in the step 1) into a ketone solvent to separate out a solid, thereby obtaining a citrate crystal form 18.
In yet another aspect of the invention, the invention also provides a crystalline form 20 of the citrate salt of the compound of formula (I). According to an embodiment of the present invention, the crystalline form 20 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 8.5 degrees +/-0.2 degree, 15.7 degrees +/-0.2 degree and 21.1 degrees +/-0.2 degree.
According to an embodiment of the present invention, the above-mentioned crystalline form 20 may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the crystalline form 20 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 8.5 degrees +/-0.2 degree, 15.7 degrees +/-0.2 degree, 17.2 degrees +/-0.2 degree, 18.7 degrees +/-0.2 degree, 19.0 degrees +/-0.2 degree and 21.1 degrees +/-0.2 degree.
According to an embodiment of the present invention, the crystalline form 20 has an X-ray powder diffraction pattern substantially as shown in figure 3.
In yet another aspect of the present invention, a method of preparing crystalline form 20 of citrate is also presented. According to an embodiment of the invention, the method comprises: dissolving citrate of the compound shown in the formula (I) in N-methyl pyrrolidone, placing the solution in an ester solvent atmosphere for gas-liquid permeation, and after 1-2 weeks, separating out solids to obtain a citrate crystal form 20.
In yet another aspect of the present invention, the present invention also provides crystalline form 23 of the citrate salt of the compound of formula (I). According to an embodiment of the present invention, the crystalline form 23 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 13.5 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees and 21.6 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the above form 23 may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the crystalline form 23 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 8.7 degrees +/-0.2 degrees, 12.3 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees and 26.6 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the crystalline form 23 has an X-ray powder diffraction pattern substantially as shown in figure 4.
In yet another aspect of the present invention, a method of preparing crystalline form 23 of citrate is also presented. According to an embodiment of the invention, the method comprises: dissolving citrate of a compound shown in a formula (I) in N, N-dimethylacetamide, placing the solution in an ester solvent atmosphere for gas-liquid permeation, and after 1-2 weeks, separating out solids to obtain a citrate crystal form 23.
In yet another aspect of the present invention, there is also provided crystalline form 26 of the citrate salt of the compound of formula (I), wherein the crystalline form 26 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 7.5 degrees +/-0.2 degrees, 12.5 degrees +/-0.2 degrees and 16.7 degrees +/-0.2 degrees.
According to an embodiment of the present invention, the above-mentioned crystalline form 26 may further include at least one of the following additional technical features:
according to an embodiment of the present invention, the crystalline form 26 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.5 degrees +/-0.2 degree, 7.5 degrees +/-0.2 degree, 12.5 degrees +/-0.2 degree, 13.1 degrees +/-0.2 degree, 15.9 degrees +/-0.2 degree and 16.7 degrees +/-0.2 degree.
According to an embodiment of the present invention, the crystalline form 26 has an X-ray powder diffraction pattern substantially as shown in figure 5.
In yet another aspect of the present invention, a method of preparing crystalline form 26 of citrate salt is also presented. According to an embodiment of the invention, the method comprises: the compound of formula (I) and citric acid are stirred in a mixture solvent of alcohol and halogenated hydrocarbon at the temperature of 20-30 ℃ for 1-3 days, and then solid is separated to obtain the citrate crystal form 26.
In yet another aspect of the invention, a pharmaceutical composition is also provided. According to an embodiment of the invention, the pharmaceutical composition comprises: form 13 as hereinbefore described or form 13 as hereinbefore prepared by the process as hereinbefore described or form 18 as hereinbefore prepared by the process as hereinbefore described or form 20 as hereinbefore described or form 23 as hereinbefore prepared by the process as hereinbefore described or form 23 as hereinbefore prepared or form 26 as hereinbefore described or form 26 as hereinbefore prepared by the process as hereinbefore described.
In a further aspect of the present invention, the present invention also provides the use of the aforementioned crystalline form 13 or the crystalline form 13 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 18 or the crystalline form 18 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 20 or the crystalline form 23 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 26 or the aforementioned pharmaceutical composition for preparing a P2X3 inhibitor.
In a further aspect of the present invention, the present invention also provides the use of the aforementioned crystalline form 13 or the crystalline form 13 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 18 or the crystalline form 18 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 20 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 23 or the crystalline form 23 obtained by the preparation according to the aforementioned method or the aforementioned crystalline form 26 or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing or treating refractory chronic cough and unexplained chronic cough.
Definitions and explanations
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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a special physical form of a solid substance, with locally ordered structural features suggesting that it has a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.
By "antisolvent" is meant a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" means a crystal having a solvent on the surface, or in the crystal lattice, or on the surface and in the crystal lattice, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloro alkane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the crystal lattice, or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents besides water, on the surface of the substance, or in the crystal lattice, or both.
Crystalline or amorphous forms may be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test according to the invention.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under program control 2 O 3 ) The energy difference therebetween varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC curve with characteristic peak positions substantially as shown in the DSC diagrams provided in the figures of the present invention. Meanwhile, the DSC curve may have experimental errors, and the peak position and the peak value of the DSC curve may slightly differ from instrument to instrument and from sample to sample, so the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instrument used in the test according to the invention, the melting peak has a tolerance of + -3 ℃.
Solids of the same chemical composition often form isomeric, or referred to as metamorphosis, isomers of different crystal structures under different thermodynamic conditions, and this phenomenon is called polymorphism or homomultiphase phenomenon. When the temperature and pressure conditions are changed, the variants are transformed into each other, and the phenomenon is called crystal transformation. Due to the crystal form transformation, the mechanical, electrical, magnetic and other properties of the crystal can be changed greatly. When the temperature of crystal transformation is in a measurable range, the transformation process can be observed on a Differential Scanning Calorimetry (DSC) curve, and the DSC curve is characterized by having an exothermic peak reflecting the transformation process and simultaneously having two or more endothermic peaks which are respectively characteristic endothermic peaks of different crystal forms before and after transformation. The crystalline form or amorphous form of the compounds of the present invention may undergo a crystalline form transformation under appropriate conditions.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. In some embodiments, the calcium salt form a of the present invention loses weight by about 5.1% at a temperature of about 150 ℃. There is a tolerance of + -0.3% for mass variations depending on the condition of the instrument used in the test of the invention.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
In the present invention, "room temperature" means, if not specifically mentioned, a temperature of 22 ℃ to 28 ℃.
The term "substantially as shown" means that 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 the X-ray powder diffraction pattern are shown in the figure.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean for one of ordinary skill in the art. Whenever a number with a value of N is disclosed, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.
The term "comprising" is open-ended, i.e. comprising what is specified in the invention, but does not exclude other aspects.
Drawings
Figure 1 is an XRPD pattern of form 13 according to an embodiment of the invention;
figure 2 is an XRPD pattern of form 18 according to an embodiment of the invention;
figure 3 is an XRPD pattern of form 20 according to an embodiment of the invention;
figure 4 is an XRPD pattern of form 23 according to an embodiment of the invention;
figure 5 is an XRPD pattern of crystalline form 26 according to an embodiment of the invention;
figure 6 is a TGA profile of crystalline form 13 according to an embodiment of the present invention;
figure 7 is a DSC curve for form 13 according to an embodiment of the present invention;
FIG. 8 is a crystal modification 13 according to an embodiment of the present invention 1 H NMR spectrum;
figure 9 is a TGA profile of crystalline form 18 according to an embodiment of the present invention;
fig. 10 is a DSC curve for form 18 according to an embodiment of the present invention;
FIG. 11 is a crystal form 18 according to an embodiment of the present invention 1 An H NMR spectrum;
figure 12 is an XRPD pattern of form 18 of example 3 according to an embodiment of the invention;
FIG. 13 is a crystalline form 20 according to an embodiment of the present invention 1 H NMR spectrum;
FIG. 14 is a crystalline form 23 according to an embodiment of the present invention 1 H NMR spectrum;
FIG. 15 is a crystalline form 26 according to an embodiment of the present invention 1 An H NMR spectrum;
figure 16 is a dissolution profile of form 13, form a and form B in sodium acetate buffer at pH 4.5 at 37 ℃ according to an embodiment of the present invention;
FIG. 17 is a graph comparing XRPD for crystalline form 13 according to an embodiment of the invention at 25 ℃/60% RH and 40 ℃/75% RH for 2 weeks prior to packaging conditions;
FIG. 18 is a graph comparing XRPD for crystalline form 13 according to an embodiment of the invention at 25 ℃/60% RH and 40 ℃/75% RH for 4 weeks prior to packaging conditions;
FIG. 19 is a graph comparing XRPD for crystalline form 13 according to an embodiment of the invention at 25 ℃/60% RH and 40 ℃/75% RH for 8 weeks prior to packaging conditions;
FIG. 20 is an XRPD comparison pattern for 4 weeks of crystalline form 13 according to an embodiment of the invention at 25 ℃,11% RH, 32% RH and 57% RH conditions;
FIG. 21 is a graph comparing the XRPD of form A according to an example of the invention at 25 ℃,11% RH, 32% RH and 57% RH for 4 weeks;
FIG. 22 is an XRPD comparison pattern for crystal form B according to an embodiment of the invention at 25 ℃,11% RH, 32% RH and 57% RH conditions for 4 weeks;
FIG. 23 is an XRPD comparison pattern for crystalline form 13 according to the examples of the present invention at 25 ℃,100% RH conditions for 2 weeks;
fig. 24 is a DVS profile of form 13 according to an embodiment of the present invention.
Detailed Description
The present application is described in detail below by way of examples, but there is no intention to be bound by any adverse limitation to the present application. Having described the present application in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
The starting materials used in the present invention are commercially available unless otherwise specified.
The abbreviations used in the present invention are explained as follows:
XRPD: powder X-ray diffraction
DSC: differential scanning calorimetry
TGA: thermogravimetric analysis
1 H NMR: liquid hydrogen spectrum nuclear magnetic
HPLC: high performance liquid chromatography
The X-ray powder diffraction range of the invention is collected on a Bruker (Bruker) model D8 ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
an X-ray light source: cu, K alpha
The K alpha 2/K alpha 1 intensity ratio: 0.5
Voltage: 40 kilovolt (kV)
Current: 10 milliampere (mA)
Scanning range: from 3.0 to 50.0 degrees
The differential scanning calorimeter curve of the invention is collected on a DSC3 type differential scanning calorimeter of Mettler company. The parameters of the differential scanning calorimetry analysis method are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
The thermogravimetric analysis curve of the invention is collected on an SDT Q600 type synchronous thermal analyzer of TA company. The parameters of the thermogravimetric analysis method are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
The High Performance Liquid Chromatography (HPLC) data in the present invention is from Thermo U3000 and the detector used is a uv detector (VWD). The HPLC method parameters for testing purity and solubility of the present invention are as follows:
a chromatographic column: agilent Eclipse XDB C18, 4.6X 150 mm, 3.5 micron
Mobile phase: a0.1% phosphoric acid aqueous solution
B is acetonitrile
The elution gradient is shown in table 1 below:
TABLE 1
| Time (minutes) | |
| 0 | 10 |
| 5 | 40 |
| 11 | 90 |
| 15 | 90 |
| 15.1 | 10 |
| 20 | 10 |
Flow rate: 1.0 ml/min
Sample introduction amount: 3 microliter
Detection wavelength: 254 nm
Column temperature: 30 deg.C
Diluent (b): DMSO/H2O (volume ratio 8:2)
Dissolution rate data in the present invention were collected on a dissolution apparatus model 708D/850DS from Agilent. The intrinsic dissolution test conditions are shown in table 2 below:
TABLE 2
The compound (I) starting materials used in the following examples can be prepared according to the prior art. For example, the compound is prepared according to the method described in CN1930135B, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
Example 1 preparation of citrate form 13
Weighing 5 g of a solid compound of the formula (I) at room temperature, placing the solid compound in a round bottomIn the flask, 50 ml of absolute ethanol was added, and stirring was performed under magnetic force. 3.6 g of citrate monohydrate was weighed and dissolved by adding 2.5 ml of water. The aqueous solution of the citrate is added to an absolute ethanol mixture of the compound of the formula (I), stirred for 3 hours and then filtered by suction. The filter cake was rinsed with 20 ml of absolute ethanol and then dried under vacuum at 30 ℃. Taking 1.5 g of the dried sample, putting the dried sample into a dryer filled with pure water for gas-solid permeation, and taking out the sample after 8 days to obtain the citrate crystal form 13. The X-ray powder diffraction data are shown in Table 3, and the diffraction pattern is shown in FIG. 1. TGA data is shown in FIG. 6, DSC data is shown in FIG. 7, 1 the H NMR data are shown in FIG. 8.
TABLE 3
Examples 2 to 3: preparation of citrate form 18
Example 2: 100.9 mg of the compound of formula (I) citrate solid are placed in a glass vial at room temperature and dissolved by adding 0.3 ml of N-methylpyrrolidone. The clear solution was then magnetically stirred (speed of about 1000 rpm) and 1 ml of isopropyl acetate was added dropwise to precipitate a solid, giving form 18 of citrate. The X-ray powder diffraction data are shown in Table 4, and the diffraction pattern is shown in FIG. 2. TGA data is shown in FIG. 9, DSC data is shown in FIG. 10, 1 the H NMR data are shown in FIG. 11.
TABLE 4
Example 3: 252.5 mg of the citrate solid of the compound of formula (I) were placed in a glass vial at room temperature and dissolved by adding 0.5 ml of N-methylpyrrolidone. And then dripping the clear solution into 1.875 ml of 2-butanone precooled at 4 ℃, magnetically stirring at 4 ℃ (the rotating speed is about 1000 revolutions per minute) overnight to precipitate a solid, standing the suspension at-30 ℃ for about 7 hours, performing suction filtration to obtain a solid, and transferring the solid to 40 ℃ for drying for about 7 hours to obtain the citrate crystal form 18. The X-ray powder diffraction data are shown in table 5, and the diffraction pattern is shown in fig. 12.
TABLE 5
Example 4: preparation of citrate form 20
500 mg of the compound of formula (I) as a citrate solid is weighed, 12.5 ml of N-methylpyrrolidone is added, and after 5 minutes of sonication, the solution is cleared. And equally dividing the clear solution into 7 parts, putting 1 part of the clear solution into an atmosphere of 4 ml of isopropyl acetate, performing gas-liquid permeation, and separating out solids after 1-4 weeks to obtain the citrate crystal form 20. The X-ray powder diffraction data are shown in Table 6, the diffraction pattern is shown in FIG. 3, 1 the H NMR data are shown in FIG. 13.
TABLE 6
| Angle of |
d value | Strength% |
| 5.13 | 17.22 | 4.50 |
| 8.27 | 10.68 | 8.90 |
| 8.52 | 10.37 | 100.00 |
| 15.74 | 5.63 | 83.90 |
| 16.96 | 5.22 | 2.80 |
| 17.22 | 5.15 | 19.50 |
| 18.66 | 4.75 | 7.70 |
| 19.02 | 4.66 | 5.90 |
| 21.10 | 4.21 | 47.40 |
| 21.75 | 4.08 | 2.50 |
| 22.82 | 3.89 | 2.90 |
| 23.03 | 3.86 | 1.70 |
| 23.59 | 3.77 | 5.60 |
| 26.04 | 3.42 | 5.00 |
| 26.53 | 3.36 | 2.60 |
| 26.81 | 3.32 | 8.40 |
| 27.24 | 3.27 | 3.60 |
| 28.66 | 3.11 | 3.40 |
| 32.01 | 2.79 | 3.50 |
| 33.91 | 2.64 | 2.40 |
| 35.32 | 2.54 | 1.40 |
| 39.76 | 2.27 | 1.30 |
| 40.44 | 2.23 | 2.10 |
| 43.14 | 2.10 | 1.60 |
| 43.87 | 2.06 | 1.30 |
Example 5: preparation of citrate form 23
500 mg of the compound of formula (I) as a citrate solid was weighed, 12.5 ml of N, N-dimethylacetamide was added, and the mixture was sonicated for 5 minutes and then cleared. And equally dividing the clear solution into 7 parts, putting 1 part of the clear solution into 4 ml of isopropyl acetate, performing gas-liquid permeation, and after 1-4 weeks, separating out solids to obtain the citrate crystal form 23. The X-ray powder diffraction data are shown in Table 7, the diffraction pattern is shown in FIG. 4, 1 the H NMR data are shown in FIG. 14.
TABLE 7
Example 6: preparation of citrate crystalline form 26
Weighing 51.3 mg of the compound of formula (I) and 1.1 times molar equivalent of citric acid as a solid, adding 0.5 ml of a mixed solvent of methanol/dichloromethane (volume ratio 1:1), magnetically stirring (about 1000 rpm) overnight, and centrifuging the solid to obtain the citrate form 26. The X-ray powder diffraction data are shown in Table 8, the diffraction pattern is shown in FIG. 5, 1 the H NMR data are shown in FIG. 15.
TABLE 8
Example 6: solubility of the Crystal form
Respectively preparing the crystal form 13 of the invention and the crystal forms A and B disclosed in the prior art into turbid liquids by using SGF (simulated artificial gastric juice), faSSIF (artificial intestinal juice in a fasting state) and pure water, balancing at 37 ℃ for 4 hours and 24 hours, and filtering to obtain saturated solutions. The content of the compound in the saturated solution was measured by high performance liquid chromatography. From the results, it is clear that the solubility of form 13 of the present invention in SGF, faSSIF and pure water is higher than that of forms a and B disclosed in the prior art. The solubility data are shown in Table 9.
TABLE 9
Example 7: dissolution profile of the crystalline form
The crystal form 13 of the present invention and the crystal forms a and B disclosed in the prior art are weighed to be each about 100mg and filled into gelatin empty capsule shells, and each crystal form is filled in two parts in parallel. Transferring the filled capsule to a dissolution instrument to test a dissolution curve. The dissolution conditions are shown in table 10, and dissolution curves are plotted from the dissolution data results, as shown in fig. 16. The results show that the dissolution rate of form 13 of the present invention is faster than both forms a and B disclosed in the prior art.
TABLE 10
Example 8: stability of form 13 at 25 ℃/60% RH and 40 ℃/75% RH for 8 weeks
The crystal form 13 of the present invention was weighed, placed in a stabilization box at 25 ℃/60% rh and 40 ℃/75% rh respectively after open/vacuum packaging/nitrogen-filled packaging, sampled at regular times to test XRPD and HPLC purity, and the data statistics are shown in table 11, from which it can be seen that the crystal form and chemical purity of the crystal form 13 under any of the above packaging conditions can be maintained stable without significant changes, and the XRPD comparison graphs at 2 weeks, 4 weeks and 8 weeks thereof can be seen in fig. 17, 18 and 19.
TABLE 11
Example 9: stability of the crystal form at 25 ℃,11% RH, 32% RH and 57% RH for 4 weeks
The crystal form 13 of the invention and the crystal forms A and B disclosed in the prior art are weighed, and are placed in an atmosphere of a prepared saturated salt solution with the temperature of 25 ℃, the relative humidity of 11%,32% and 57% in an open manner, and the XRPD is taken out and tested after 4 weeks of gas-solid diffusion. From the results, no change occurred in the XRPD patterns of form 13, form a, and form B. The XRPD patterns are shown in FIG. 20, FIG. 21 and FIG. 22.
Example 10: stability of form 13 at 25 ℃,100% RH for 2 weeks
The crystal form 13 of the present invention was weighed, left open in a room at 25 ℃ with a relative humidity of 100% (pure water environment), and taken out after 2 weeks to test XRPD. From the results, the XPRD pattern of form 13 was unchanged, and the XRPD pattern thereof is shown in fig. 23.
Example 11
Placing the crystal form 13 in a sample tank of DVS, after the mass reaches constant weight under the condition of 25C,50% RH, keeping the temperature unchanged, increasing the mass to 95% RH step by taking 5% RH as a unit, entering the next target humidity after the mass of the sample is constant weight at each relative humidity, and entering the next target humidity after the mass of the sample is constant weight; similarly, when the relative humidity reached 95% RH and the mass was constant, the relative humidity was reduced from 95% RH to 0% RH in units of 5% RH; then, from 0% RH liter to 95% RH in units of 5-RH. The mass data at each relative humidity were recorded separately to obtain DVS curves (fig. 24).
As shown in fig. 23, when the relative humidity was 50%, the mass increased by 5.6% compared to two molecules of water (mass% 6.2%). When the relative humidity is 90%, the mass is increased by 7%, which is similar to the mass percentage of water of two molecules.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Form 13 of the citrate salt of a compound of formula (I), characterized in that the form 13 has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees and 14.6 degrees +/-0.2 degrees,
2. a crystalline form 13 according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystalline form 13 has characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees and 20.4 degrees +/-0.2 degrees.
3. A crystalline form 13 according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystalline form 13 has characteristic diffraction peaks at the following 2 Θ angles: 7.2 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 14.6 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees and 25.5 degrees +/-0.2 degrees.
4. A crystalline form 13 according to claim 1, characterized in that the form 13 has an X-ray powder diffraction pattern substantially as shown in figure 1.
5. The crystalline form 13 according to claim 1, wherein the crystalline form 13 is a hydrate, and wherein the moisture content is from 5.0% to 7.0%.
6. The crystalline form 13 according to claim 1, wherein the crystalline form 13 is a dihydrate.
7. A method of preparing form 13 citrate salt, comprising:
1) Suspending and stirring the compound of formula (I) and citric acid aqueous solution in alcohol solvent for 1-5 hours, separating and drying to obtain solid,
2) And (3) placing the solid in a pure water solvent atmosphere for gas-solid diffusion, wherein the gas-solid diffusion is carried out for 1 to 10 days at the temperature of 20 to 30 ℃ to obtain the citrate crystal form 13.
8. A pharmaceutical composition, comprising: form 13 according to any one of claims 1 to 6 or form 13 when prepared according to the process of claim 7.
9. Use of the crystalline form 13 according to any one of claims 1 to 6 or the crystalline form 13 prepared by the process according to claim 7 or the pharmaceutical composition according to claim 8 in the preparation of a P2X3 inhibitor.
10. Use of the crystalline form 13 according to any one of claims 1 to 6 or the crystalline form 13 obtained by the process according to claim 7 or the pharmaceutical composition according to claim 8 for the preparation of a medicament for the prevention or treatment of refractory chronic cough and chronic cough of unknown cause.
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