CN113912565A - Novel crystal form of cariprazine and preparation method thereof - Google Patents
Novel crystal form of cariprazine and preparation method thereof Download PDFInfo
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- CN113912565A CN113912565A CN202110776423.2A CN202110776423A CN113912565A CN 113912565 A CN113912565 A CN 113912565A CN 202110776423 A CN202110776423 A CN 202110776423A CN 113912565 A CN113912565 A CN 113912565A
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a crystal form of cariprazine and a preparation method thereof; the crystal form of the cariprazine has good stability, and can be used for developing long-acting injection and other pharmaceutical preparations; the preparation method is simple to operate and can be used for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a crystal form of cariprazine and a preparation method thereof.
Background
Carilazine (Cariprazine, CAS number 839712-12-8) has the chemical name 3- [4- [2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] ethyl ] cyclohexyl ] -1, 1-dimethylurea, and has the following structural formula:
the drug is a psychiatric drug developed by Actavis and Gedeon Richter. The cariprazine hydrochloride formulation was approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults at 9 months 2015. A Crystal form of Cariprazine free base is reported in the prior art of Crystal Structures and Thermodynamic Properties of New orthopedic antibacterial Cariprazine and Its Hydrochloride; and the free base trihydrate crystal form is disclosed in Tianjin Han Kongquass patent CN 201510773565.8.
The API solid form of the currently marketed kalilazine drug is the hydrochloride, the free base form of kalilazine has a lower solubility, and the free base can be used for developing pharmaceutical formulations such as long acting injections, etc. by utilizing the characteristic that the free base has a relatively lower solubility. The invention provides a crystal form I of cariprazine, which can be used for preparing long-acting injection and other pharmaceutical preparations; the invention also provides a preparation method of the crystal form I, which is simple to operate and can be used for industrial production.
Summary of The Invention
In a first aspect, the invention provides a crystalline form of cariprazine, designated form I.
Compared with the crystal form I of the cariprazine in the prior art, the crystal form I of the cariprazine provided by the invention has good stability, and can be used for developing long-acting injection and other pharmaceutical preparations.
The X-ray powder diffraction pattern of the crystal form I of the cariprazine provided by the invention comprises diffraction peaks with 2theta angles of 4.21, 16.58, 24.95 and 29.18 degrees. In some embodiments, the crystalline form I of carpilazine comprises diffraction peaks in an X-ray powder diffraction pattern at 2 Θ angles of 4.21, 8.32, 12.44, 16.58, 24.95, and 29.18 degrees. In some embodiments, the crystalline form I of carpilazine comprises diffraction peaks in an X-ray powder diffraction pattern at 2 Θ angles of 4.21, 5.78, 8.32, 11.51, 12.44, 16.58, 24.95, 29.18, 33.45, 37.79, and 42.15 degrees.
In some embodiments, the crystalline form I of cariprazine has an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the present invention provides a crystalline form I of cariprazine having a differential scanning calorimetry curve with endothermic peaks in the range of 65 ℃ to 75 ℃ and in the range of 210 ℃ to 220 ℃. In some embodiments, the differential scanning calorimetry curve of crystalline form I of the calicheazine of the present invention has a broader endothermic peak at 65 ℃ to 75 ℃ and a sharper endothermic peak in the range of 210 ℃ to 220 ℃.
In some embodiments, the differential scanning calorimetry curve of crystalline form I of carpilazine has endothermic peaks at 71.56 ℃ and at 214.20 ℃. In some embodiments, the differential scanning calorimetry curve of crystalline form I of the calicheazine of the present invention has a broader endothermic peak at 71.56 ℃ and a sharper endothermic peak at 214.20 ℃.
In some embodiments, the differential scanning calorimetry curve of the crystalline form I of cariprazine is substantially as shown in figure 2.
In some embodiments, the crystalline form I of cariprazine, whose thermogravimetric analysis curve shows a 3.8% to 4.2% weight loss of crystalline form I over the temperature range of 25 ℃ to 100 ℃.
In some embodiments, the crystalline form I of cariprazine has a thermogravimetric analysis curve that shows a weight loss of about 4.0% for crystalline form I over a temperature range of 20 ℃ to 150 ℃.
In some embodiments, the crystalline form I of cariprazine is considered to be a monohydrate crystalline form as calculated from its DSC and TGA profiles. According to some embodiments of the invention, the crystalline form I of cariprazine is cariprazine monohydrate.
In some embodiments, the crystalline form I of cariprazine has a thermogravimetric analysis curve substantially as shown in figure 3.
In a second aspect of the invention, a process for preparing crystalline form I of cariprazine is provided. The preparation method is simple, convenient to operate, mild in condition, good in repeatability and suitable for industrial production.
A method of preparing crystalline form I of cariprazine, comprising: under the condition of high temperature, the cariprazine is dissolved in a good solvent to form a high-temperature solution, then the obtained high-temperature solution is added into a poor solvent with a lower temperature, the filtration is carried out, and the obtained solid is dried to obtain the crystal form I.
In some embodiments, a method of making crystalline form I of cariprazine, comprising: under the condition of high temperature, the cariprazine is dissolved in a good solvent with a certain volume, the obtained high-temperature solution is dissolved out in a poor solvent, the filtration is carried out, and the obtained solid is dried to obtain the crystal form I of the cariprazine.
In some embodiments, a method of making crystalline form I of cariprazine, comprising: under the condition of high temperature, the cariprazine is dissolved in a good solvent to form a high-temperature solution of the cariprazine and the good solvent in a certain proportion, then the obtained high-temperature solution is added into a poor solvent with a lower temperature, the filtration is carried out, and the obtained solid is dried, such as blow-drying by nitrogen, so as to obtain the crystal form I.
The good solvent is at least one selected from methanol, ethanol, N-propanol, tetrahydrofuran, N, N-dimethylformamide and N, N-dimethylacetamide. In some embodiments, the good solvent is methanol. In some embodiments, the good solvent is ethanol. In some embodiments, the good solvent is n-propanol. In some embodiments, the good solvent is tetrahydrofuran.
The poor solvent is water.
The high temperature is 60-80 ℃. In some embodiments, the high temperature dissolution temperature ranges from 60 ℃ to 75 ℃. In some embodiments, the high temperature dissolution temperature ranges from 60 ℃ to 70 ℃. In some embodiments, the high temperature dissolution temperature ranges from 60 ℃ to 65 ℃. In some embodiments, the high temperature dissolution temperature ranges from 65 ℃ to 75 ℃. In some embodiments, the high temperature dissolution temperature range is 60 ℃. In some embodiments, the high temperature dissolution temperature range is 65 ℃. In some embodiments, the high temperature dissolution temperature range is 70 ℃. In some embodiments, the high temperature dissolution temperature range is 75 ℃. In some embodiments, the high temperature dissolution temperature range is 80 ℃.
The ratio range of the Carilazine to the good solvent in the high-temperature solution is 10.0mg/mL-30.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 10.0mg/mL to 25.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 10.0mg/mL to 20.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 10.0mg/mL to 15.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 15.0mg/mL to 30.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 15.0mg/mL to 25.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 15.0mg/mL to 20.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 20.0mg/mL to 30.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution ranges from 20.0mg/mL to 25.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 10.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 15.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 16.7 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 20.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 25.0 mg/mL. In some embodiments, the ratio of the cariprazine to the good solvent in the high temperature solution is 30.0 mg/mL.
The lower temperature of the invention is 0-30 ℃. In some embodiments, the lower temperature range is from 0 ℃ to 25 ℃; in some embodiments, the lower temperature range is 0 ℃ to 20 ℃; in some embodiments, the lower temperature range is 0 ℃ to 15 ℃; in some embodiments, the lower temperature range is 0 ℃ to 10 ℃; in some embodiments, the lower temperature range is 0 ℃ to 5 ℃; in some embodiments, the lower temperature range is 5 ℃ to 30 ℃; in some embodiments, the lower temperature range is from 5 ℃ to 25 ℃; in some embodiments, the lower temperature range is 5 ℃ to 20 ℃; in some embodiments, the lower temperature range is 5 ℃ to 15 ℃; in some embodiments, the lower temperature range is 5 ℃ to 10 ℃; in some embodiments, the lower temperature range is 10 ℃ to 30 ℃; in some embodiments, the lower temperature range is from 10 ℃ to 25 ℃; in some embodiments, the lower temperature range is from 10 ℃ to 20 ℃; in some embodiments, the lower temperature range is 10 ℃ to 15 ℃; in some embodiments, the lower temperature range is 15 ℃ to 30 ℃; in some embodiments, the lower temperature range is 15 ℃ to 25 ℃; in some embodiments, the lower temperature range is 15 ℃ to 20 ℃; in some embodiments, the lower temperature range is 20 ℃ to 30 ℃; in some embodiments, the lower temperature range is 20 ℃ to 25 ℃; in some embodiments, the lower temperature range is 25 ℃ to 30 ℃; in some embodiments, the lower temperature range is 0 ℃; in some embodiments, the lower temperature range is 5 ℃; in some embodiments, the lower temperature range is 10 ℃; in some embodiments, the lower temperature range is 15 ℃; in some embodiments, the lower temperature range is 20 ℃; in some embodiments, the lower temperature range is 25 ℃; in some embodiments, the lower temperature range is 30 ℃.
In some embodiments, a method of making crystalline form I of cariprazine, comprising: dissolving the cariprazine in a good solvent at the temperature of 60-80 ℃ to form a high-temperature solution of the cariprazine and the good solvent in a certain proportion, then adding the obtained high-temperature solution into water at the temperature of 0-30 ℃, filtering, and drying the obtained solid by blowing with nitrogen to obtain the crystal form I.
In some embodiments, a method of making crystalline form I of cariprazine, comprising: dissolving cariprazine in a good solvent at 70 ℃ to form a high-temperature solution of the cariprazine and the good solvent in a certain proportion, adding the obtained high-temperature solution into purified water at 5 ℃, filtering, and drying the obtained solid by using nitrogen to obtain a crystal form I; the good solvent may be at least one of methanol, ethanol, n-propanol and tetrahydrofuran.
The temperature of the drying may be room temperature. In some embodiments, the solid is dried at 0 ℃ to 30 ℃. In some embodiments, the solid is blow dried at 0 ℃ to 30 ℃ with nitrogen.
In another aspect, the present invention provides a pharmaceutical composition, which comprises the aforementioned crystalline form I and a pharmaceutically acceptable excipient. In some embodiments, form I is 0.05% to 99% or 5% to 95% of the cariprazine in the composition, based on the total weight of the cariprazine.
Definition of terms
"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.
"good solvent" or "solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
"poor solvent" or "antisolvent" refers to 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. In some embodiments, the solubility of the cariprazine in a good solvent is greater than that of a poor solvent; in some embodiments, the difference between the solubility of the good solvent and the poor solvent for the cariprazine is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
Crystalline forms or amorphous forms can 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 methods, 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. The 2 θ measurement of the XRPD pattern may be subject to experimental error, and may vary slightly from instrument to instrument and from sample to sample, so that the 2 θ values cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test. 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.
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 the control of a program2O3) 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. The DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so the peak position or peak value of the DSC endotherm cannot be considered absolute. The melting peak has a tolerance of + -3 deg.C depending on the condition of the instrument used in the test. In some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention.
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. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
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.
In the context of the present invention, the diffraction angle 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (. degree.).
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.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. Based on the disclosed numbers, there may be differences of 1%, 2%, or 5% in the value of each number.
The term "room temperature" means a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
In the present invention, mg/mL means mg/mL, h means hour, mg means mg, mL means mL, DEG C means centigrade, and mL/min means mL/min.
Drawings
Figure 1 shows an XRPD spectrum of crystalline form I of cariprazine with the abscissa representing 2 θ angle, units degrees (°), and the ordinate representing relative intensity counts (intensity (counts)).
FIG. 2 shows a DSC spectrum of crystalline form I of cariprazine with the abscissa representing temperature in degrees C and the ordinate representing Heat Flow in watts/gram (W/g).
Figure 3 shows a TGA spectrum of crystalline form I of cariprazine with the abscissa representing temperature and the unit c and the ordinate representing the percent Weight loss (Weight,%).
Figure 4 shows an XRPD spectrum of an anhydrous crystalline form of cariprazine with the abscissa representing 2 θ angle, units degrees (°), and the ordinate representing relative intensity counts (intensity (counts)).
FIG. 5 shows a DSC spectrum of an anhydrous crystalline form of cariprazine with the abscissa indicating temperature in degrees Celsius and the ordinate indicating Heat Flow in watts/gram (W/g).
Figure 6 shows a TGA spectrum of an anhydrous crystalline form of cariprazine in degrees celsius with the ordinate indicating the percent Weight loss (Weight,%).
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.
Example 1
Weighing 50.0mg of cariprazine, placing the weighed cariprazine in a 5mL EP tube, adding 3.0mL of methanol solvent, stirring at 64 ℃ and 200rpm magnetically until the solid is completely dissolved to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water at 25.0 ℃ and 200rpm magnetically, crystallizing, filtering, drying the obtained solid with nitrogen, and obtaining 22.5mg of crystal form I of the cariprazine, wherein the detection spectrum of the crystal form I is consistent with that of the attached figure 1-3.
Example 2
Weighing 50.0mg of cariprazine, placing the weighed cariprazine in a 5mL EP tube, adding 3.0mL of ethanol solvent, stirring at 78.0 ℃ and 200rpm magnetically to completely dissolve the solid to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water at 25.0 ℃ and 200rpm magnetically to crystallize, filtering, drying the obtained solid with nitrogen to obtain 23.3mg of crystal form I of the cariprazine, wherein the detection spectrum of the crystal form I is consistent with that of the attached figure 1-3.
Example 3
Weighing 50.0mg of cariprazine, placing the weighed cariprazine into a 5mL EP tube, adding 3.0mL of n-propanol solvent, dissolving the solid completely under the magnetic stirring condition of 200rpm at 80.0 ℃ to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water under the magnetic stirring condition of 200rpm at 25.0 ℃ to crystallize, filtering, and drying the obtained solid by blowing with nitrogen to obtain 20.6mg of crystal form I of the cariprazine.
Example 4
Weighing about 50.0mg of cariprazine, placing the weighed cariprazine into a 5mL EP tube, adding about 3.0mL of tetrahydrofuran solvent, dissolving the solid completely under the magnetic stirring condition of 200rpm at 65.0 ℃ to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water under the magnetic stirring condition of 200rpm at 25.0 ℃ to crystallize, filtering, and drying the obtained solid by blowing with nitrogen to obtain 20.3mg of crystal form I of the cariprazine.
Example 5
Weighing 50.0mg of cariprazine, placing the weighed cariprazine into a 5mL EP tube, adding 3.0mL of n-propanol solvent, dissolving the solid completely under the magnetic stirring condition of 200rpm at 70.0 ℃ to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water under the magnetic stirring condition of 200rpm at 15.0 ℃ to crystallize, filtering, and drying the obtained solid by blowing with nitrogen to obtain 25.2mg of crystal form I of the cariprazine.
Example 6
Weighing about 50.0mg of cariprazine, placing the weighed cariprazine into a 5mL EP tube, adding about 3.0mL of n-propanol solvent, dissolving the solid completely under the magnetic stirring condition of 200rpm at 70.0 ℃ to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water under the magnetic stirring condition of 200rpm at low temperature of about 5.0 ℃ for crystallization, filtering, and blowing the obtained solid with nitrogen to obtain 25.8mg of crystal form I of the cariprazine.
Example 7
Weighing about 50.0mg of cariprazine, placing the weighed cariprazine into a 5mL EP tube, adding about 3.0mL of tetrahydrofuran solvent, stirring at 60.0 ℃ and 200rpm magnetically to completely dissolve the solid to form high-temperature solution, dropwise adding the obtained high-temperature solution into 3.0mL of purified water at low temperature of about 5.0 ℃ and 200rpm magnetically to crystallize, filtering, and drying the obtained solid by blowing with nitrogen to obtain 23.3mg of crystal form I of the cariprazine.
Example 8
According to the guiding principle of the stability test of the pharmaceutical preparation, the crystal form I of the Carilazine is subjected to influence factor tests including a high temperature test, a high humidity test and a strong light irradiation test, and the stability conditions influencing the crystal form are investigated.
High-temperature test: respectively taking a proper amount of the Carilazine crystal form I sample, flatly placing the sample in a weighing bottle, placing the sample in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, then respectively taking about 10mg of the sample in 5, 10 and 15 days, and testing the crystal form condition of the sample.
High humidity test: respectively taking a proper amount of the Carilazine crystal form I samples, flatly placing the samples in a weighing bottle, placing the samples in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, then respectively taking about 10mg of the samples in 5 days, 10 days and 15 days, and testing the crystal form conditions of the samples.
And (3) illumination test: respectively taking a proper amount of the cariprazine crystal form I sample, flatly spreading the sample into a weighing bottle, and carrying out ultraviolet irradiation on the sample under the conditions of visible light 4500Lux +/-500 Lux and ultraviolet light 1.7W x h/m2The sample was placed in a constant temperature and humidity chamber (25 ℃, RH60 + -5%), and about 10mg of the sample was taken at 5, 10 and 15 days, respectively, to test the crystal form.
The influence factor test results of the crystal form I of the cariprazine are respectively shown in Table 1.
Table 1: experimental result of influence factors of crystal form I of cariprazine
According to the results, the crystal form I keeps the original crystal form under high-humidity and light conditions, but is converted into an anhydrous crystal form under high-temperature conditions (the XRPD, DSC and TGA of the crystal form I are shown in figures 4, 5 and 6), and the crystal form I of the cariprazine is unstable at high temperature but is relatively stable under high-humidity and light conditions; it can be used for preparing injection or long-acting injection.
Unless otherwise specified in the parameters, all analyses were performed at room temperature in the present invention. The instrument parameters, test conditions and results were characterized as follows:
x-ray powder diffraction (XRPD)
Equipped with automated 3 x 15 zero background sample holdersAn X-ray powder diffraction (XRPD) pattern was collected on a PANALYtic Empyrean X-ray diffractometer on a transmission reflection sample stage. The radiation source is
: 1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10mm, with a theta-theta continuous scanning mode, yielding an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate is diffraction intensity expressed in counts (counts), and the abscissa is diffraction angle 2 θ expressed in degrees (°).
Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter Q2000. The sample (about 1mg to 3mg) was placed in an aluminum pan and the weight was accurately recorded. The pan was covered with a lid and then crimped and the sample was transferred to the instrument for measurement. The sample cell was equilibrated at 30 deg.C and heated to a final temperature of 300 deg.C at a rate of 50 deg.C/min under a nitrogen purge. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the Heat Flow (W/g) released per unit mass of a substance.
Thermogravimetric analysis (TGA)
Thermogravimetric analysis was performed using a TA Instruments thermogravimetric analyzer Q500, placing the appropriate amount of sample in a platinum sample pan, and increasing the temperature at a rate of 60 ℃/min under nitrogen atmosphere, with a temperature range of 30 to 300 ℃. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents mass percent (Weight%).
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. Crystalline form I of cariprazine, comprising diffraction peaks at 2 Θ angles of 4.21, 8.32, 12.44, 16.58, 24.95, and 29.18 degrees in an X-ray powder diffraction pattern.
2. Form I according to claim 1, characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 4.21, 5.78, 8.32, 11.51, 12.44, 16.58, 24.95, 29.18, 33.45, 37.79, and 42.15 degrees.
3. Form I according to claim 1, characterized by an X-ray powder diffraction pattern substantially as shown in figure 1.
4. Form I according to any one of claims 1 to 3, characterized in that it has a differential scanning calorimetry curve with endothermic peaks in the range of 65 ℃ to 75 ℃ and in the range of 210 ℃ to 220 ℃; or the thermogravimetric analysis curve shows that the weight loss of the crystal form I is 3.8-4.2% in the temperature range of 25-100 ℃.
5. The crystalline form I according to any one of claims 1-4, characterized in that it is cariprazine monohydrate.
6. A process for preparing the crystalline form I according to any one of claims 1 to 5, comprising: dissolving the cariprazine in a good solvent at the temperature of 60-80 ℃ to form a high-temperature solution of the cariprazine and the good solvent, then adding the obtained high-temperature solution into a poor solvent at the temperature of 0-30 ℃, filtering, and drying by nitrogen to obtain the crystal form I.
7. The method according to claim 6, wherein the good solvent is at least one selected from the group consisting of methanol, ethanol, N-propanol, tetrahydrofuran, N, N-dimethylformamide, and N, N-dimethylacetamide.
8. The method according to claim 6 or 7, wherein the poor solvent is water.
9. The method of any one of claims 6 to 8, wherein the ratio of the cariprazine to the good solvent in the high temperature solution is in the range of 10.0mg/mL to 30.0 mg/mL.
10. The process according to any one of claims 6 to 9, wherein the resulting high temperature solution is added to purified water at 0 ℃ to 10 ℃, filtered, and the resulting solid is blow-dried with nitrogen at room temperature to give form I; the good solvent is at least one of methanol, ethanol, n-propanol and tetrahydrofuran; the ratio range of the Carilazine to the good solvent in the high temperature solution is 15.0mg/mL-20.0 mg/mL.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2025508218A (en) * | 2022-03-17 | 2025-03-21 | アンクソ、ファーマシューティカル、カンパニー、リミテッド | Injectable depot formulations containing cariprazine free base particles - Patents.com |
| CN120289405A (en) * | 2025-04-03 | 2025-07-11 | 江苏海洋大学 | A cariprazine and quercetin drug co-crystal and its preparation method and application |
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| WO2019106490A1 (en) * | 2017-12-01 | 2019-06-06 | Aurobindo Pharma Limited | A process for the preparation of cariprazine hydrochloride |
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Cited By (2)
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| JP2025508218A (en) * | 2022-03-17 | 2025-03-21 | アンクソ、ファーマシューティカル、カンパニー、リミテッド | Injectable depot formulations containing cariprazine free base particles - Patents.com |
| CN120289405A (en) * | 2025-04-03 | 2025-07-11 | 江苏海洋大学 | A cariprazine and quercetin drug co-crystal and its preparation method and application |
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