CN108997186B - Crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 - Google Patents
Crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 Download PDFInfo
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- CN108997186B CN108997186B CN201811033114.0A CN201811033114A CN108997186B CN 108997186 B CN108997186 B CN 108997186B CN 201811033114 A CN201811033114 A CN 201811033114A CN 108997186 B CN108997186 B CN 108997186B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a novel crystal form A of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, a pharmaceutical composition containing the crystal form and application thereof. The crystal form A can be used for preparing high-selectivity calcium antagonist, and medicines for improving brain dysfunction, senile dementia, depression and learning and memory. The trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A provided by the invention has the advantages of simple preparation method operation, easy control of crystallization process, high crystallinity, good crystal form repeatability and better absorption and utilization by organisms.
Description
Technical Field
The invention relates to a novel crystal form A of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, a pharmaceutical composition containing the crystal form and application thereof.
Background
Chinese patent ZL94104879.9 discloses the compound trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, which is commonly known as 'fencroanone'. The literature discloses a synthesis method of the compound and application of the compound in preparing medicaments for resisting senile dementia and enhancing learning and memory. The chemical structural formula of the compound is as follows:
trans-4 phenyl-5-o-chlorobenzyl pyrrolidone-2
It has high selective calcium antagonistic activity on nerve cells, and has effects of improving brain dysfunction, treating senile dementia, and enhancing learning and memory. Chinese patent 94104879.9 discloses its synthesis method and its application in preparing medicine for resisting senile dementia and enhancing learning and memory, patents 97123417.5 and 97123419.1 disclose its improved synthesis method, patent 200510011028.6 discloses its application in preparing medicine for treating depression, and patent 02133429.3 discloses a method for resolving dl-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 into levorotatory and dextrorotatory monomers by using enzymatic reaction.
The crystal form of the compound can affect the stability, water solubility, storage stability, preparation easiness and the like of a pharmaceutical preparation, so that the research on the crystal form of the medicine is also important in the research and development of new medicines. No report about the crystal form of the compound exists at present. Later research and development shows that the compound has different crystal forms. Compared with a sample prepared by the synthesis method disclosed in Chinese patent 94104879.9, the crystal form A (namely the crystal form of the invention) can obviously improve the bioavailability of gastrointestinal tract administration.
Disclosure of Invention
The invention aims to provide a crystal form of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, namely a crystal form A. The compound is represented by the formula:
the single crystal X-ray diffraction spectrum of the crystal form is shown in figure 2.
The single crystal X-ray diffraction characterization of the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A provided by the invention shows that main diffraction peaks exist at diffraction 2 theta of 10.77, 12.06, 13.75, 17.68, 18.63, 19.38, 20.99, 21.20, 21.40, 21.64, 26.89 and 30.98 positions, and the error range of 2 theta is +/-0.2.
The differential scanning calorimetry analysis spectrum of the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A provided by the invention has an endothermic peak at 168.1 ℃.
The single crystal X-ray diffraction spectrum (XRPD) of the crystal form A provided by the invention is shown in figure 2.
The invention also provides a preparation method of the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A, which comprises the following steps: dissolving trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 in a good solvent to prepare a near-saturated solution, slowly volatilizing for crystallization or slowly cooling for crystallization, collecting crystals, and drying to obtain the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A.
The slow volatilization crystallization can adopt a method of slowly cooling a nearly saturated solution to volatilize a solvent under a natural or nearly natural condition.
The slow cooling crystallization can adopt a nearly saturated solution with the temperature of 50 ℃ being reduced to 0-5 ℃ at the speed of 0.1-0.5 ℃/min.
It will be appreciated by those skilled in the art that it is more important to control the rate of crystallization to prepare form a. In general, one skilled in the art would like to save process time, but the crystalline form of the present invention is contrary to controlling the rate of crystallization. On the basis of controlling the crystallization speed, a solvent which can well dissolve trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 can be used for preparing the crystal form of the invention.
Preferably, the good solvent is one or more of methanol, ethanol, acetone, chloroform, ethyl acetate, acetonitrile, ethyl formate, tetrahydrofuran, 1, 4-dioxane, diethyl ether, n-heptane, isopropylamine, methyl isobutyl ketone, isopropanol acetate, methyl tert-butyl ether, toluene, and 2-methyl tetrahydrofuran. The solvent can be chosen by the person skilled in the art to be suitable for use in industrial operations.
The invention also provides application of the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A in preparing high-selectivity calcium antagonists, medicaments for improving brain dysfunction diseases, senile dementia and depression, and learning and memory enhancing medicaments.
The invention also provides a pharmaceutical composition which contains the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A and a pharmaceutically acceptable carrier. The pharmaceutical composition can be tablets, capsules, granules, injections, freeze-dried powder injections, sustained-release preparations and the like, preferably, the administration route of the pharmaceutical composition is oral administration and contains 2-100mg of the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A.
The invention has the beneficial effects that the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A is provided, the preparation method is easy to control, the crystallinity is high, and the reproducibility of the crystal form is good. When the crystal form is used as a raw material to prepare the solid oral preparation, the dissolution rate of the solid preparation of the crystal form A is obviously superior to that of a sample obtained by the method of Chinese patent 94104879.9, and the bioavailability of a gastrointestinal tract administration mode can be improved. Has high selective calcium antagonistic activity on nerve cells, and has effects of improving brain dysfunction, treating senile dementia, and improving learning and memory.
Drawings
FIG. 1 shows a chemical structural formula of a trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A provided by the present invention;
FIG. 2 is a single crystal X-ray diffraction (XRPD) pattern of form A of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 provided by the present invention;
FIG. 3 is a Differential Scanning Calorimetry (DSC) chart of form A of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 provided in accordance with the present invention;
FIG. 4 is a schematic diagram of typical hydrogen bonding in the crystal form A of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 provided by the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the following examples, trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 can be prepared by known methods such as chinese patent nos. 94104879.9, 97123417.5, 97123419.1.
Examples 1-4 are examples of the preparation of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 form a.
Example 1
Taking 100mg of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 sample, preparing a 50 ℃ near saturated solution of an acetone/ethyl acetate (1:1) mixed solvent, cooling to 0 ℃ at the speed of 0.5 ℃/min for crystallization, collecting crystals, and drying to obtain the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A sample.
Diffraction data of the crystal single crystal were measured, and a diffraction preliminary experiment and diffraction data were collected by using a Bruker D8VENTURE type single crystal diffractometer (Mo/K α,
) The reaction is carried out under the temperature environment of 175K. Diffraction data were processed using the APEX3 software package. Based on 2.383 °<θ<9943 diffraction points collected over an angle of 27.477 ℃ using SAINT (Bruker, V)8.37A, after 2013) software analyzes and performs least square refinement to obtain the crystal unit cell parameters and orientation matrix. The highest theta angle for single crystal diffraction data collection was 27.837 deg., and the completeness of data collection corresponding to the maximum theta angle was 98.6%. The average signal-to-noise ratio (I/σ) of the diffraction data was 29.4. The XRPD pattern of form a was determined as shown in figure 2.
Example 2
Taking a 200mg trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 sample, preparing a 50 ℃ near saturated solution of a mixed solvent of methyl isobutyl ketone and 2-methyltetrahydrofuran (1:1), cooling to 2 ℃ at the speed of 0.3 ℃/min for crystallization, collecting crystals, and drying to obtain the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A sample.
Example 3
Taking a 200mg trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 sample, preparing a tetrahydrofuran/n-heptane (1:1) mixed solvent near-saturated solution at 50 ℃, cooling to 5 ℃ at the speed of 0.1 ℃/min for crystallization, collecting crystals, and drying to obtain the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A sample.
Example 4
Taking a 250mg sample of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, preparing a near saturated solution of an n-heptane solvent at 50 ℃, naturally placing in a fume hood, and observing the reduction of the solvent in the placing process. After several days crystals precipitated. Collecting crystals, and drying to obtain a trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A sample.
EXAMPLE 5 characterization of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 form A
Single, single crystal X-ray diffraction
The XRPD pattern of the crystalline form obtained in examples 2-4 was determined in the same manner as in example 1, showing that the crystalline form obtained in examples 2-4 was the same as in example 1.
DSC detection of crystal form A of di-trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2
DSC data were collected on a TA Discovery DSC Q2500 differential scanning calorimeter. The trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A prepared in the example 3 is detected, and the DSC detection result is shown in figure 3.
EXAMPLE 6 pharmaceutical composition
The formula of the pharmaceutical composition comprises the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A and pharmaceutically acceptable excipients, wherein the excipients comprise diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like.
The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, etc.
The wetting agent can be water, ethanol, isopropanol, etc.
The binder can be starch slurry, dextrin, syrup, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, polyvinylpyrrolidone, polyethylene glycol, etc.
The disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium bicarbonate and citric acid, sodium dodecyl sulfate, and crosslinked sodium carboxymethyl cellulose.
Lubricants and glidants may be talc, stearate, silicon dioxide, tartaric acid, liquid paraffin, and the like.
Different excipients are selected for combination according to the dosage form of the pharmaceutical composition, the pharmaceutical composition can be prepared into different dosage forms such as tablets, capsules, granules and the like after being mixed with a plurality of excipients, and the preparation method of the dosage forms such as the tablets, the capsules, the granules and the like of the pharmaceutical composition is the same as the preparation method of the conventional dosage forms such as the tablets, the capsules, the granules and the like in the field.
One of the tablets was prepared as follows:
the preparation method of the formula comprises the steps of preparing the crystal form A and 1000 tablets of the crystal form 94104879.9 of the Chinese patent according to the conventional tablet preparation method
EXAMPLE 7 dissolution test
A trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 sample is prepared according to the method disclosed in the patent CN94104879.9, and the sample is prepared into a tablet marked as tablet b) according to the method of the embodiment 6, and the dissolution experiment comparison is carried out on the tablet (the sample is prepared according to the same formula and the same method as the embodiment 6 and is marked as tablet a) prepared by the crystal form A of the invention. The method comprises the following steps: referring to the third method (small cup method) of dissolution and release determination of general rules in the four parts of the edition of "Chinese pharmacopoeia" 2015, 250ml of 30% isopropanol aqueous solution is used as a dissolution medium, the rotation speed is 100 revolutions per minute, sampling is carried out according to the method at 45 minutes, filtering is carried out through a 0.45 mu m microporous membrane, and the subsequent filtrate is taken as a test solution. Taking a proper amount of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 reference substance, dissolving with mobile phase ultrasonic wave, diluting to 0.5mg/ml, using as reference substance solution, and measuring by high performance liquid chromatography, wherein the chromatographic conditions are as follows: c18 column, purified with acetonitrile: 54 parts of water: 46 is a mobile phase; flow rate: 1.0 ml/min; column temperature: at room temperature, the detection wavelength is 230 nm. The dissolution rate of each tablet was calculated. The results are shown in Table 1.
TABLE 1 dissolution test results (dissolution/%)
The above results show that: the dissolution rate of the tablet a is obviously better than that of the tablet b.
EXAMPLE 8 in vivo bioavailability pharmacokinetic Studies of crystalline forms
Test drugs A sample of trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 (labeled sample b) prepared according to the method disclosed in patent CN94104879.9, a sample of inventive crystal form A (prepared according to example 1 and labeled sample a)
Experimental animals: kunming mice (male and female halves) weighing 20 + -2 g were purchased from the laboratory animal center of Kunming medical university (production license number: SCXK 2016-.
The experimental method comprises the following steps: the administration dose is 100mg/kg, the medicine is prepared into suspension by proper amount of Tween-80 and water, and the administration volume is 0.5ml/20g body weight by a stomach irrigator. The mice were fasted for 15h in advance, blood was collected at 5, 15min and 0.5, 1, 1.5, 2, 3, 4, 6h after administration, 15 animals were separated at each time point, serum was isolated (1 part per 3 mice serum), and the mice were stored at-20 ℃ for testing. Taking 1ml serum and measuring serum drug concentration by high performance liquid chromatography.
The determination method comprises the following steps: chromatographic conditions are as follows: column Spherisorb CN 10 μm, 250X 4.6mm (L X ID), mobile phase 10mmol/L ammonium acetate methanol 62:38(v/v), flow rate 0.7 ml/min. And taking a proper amount of a trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 reference substance, and diluting the reference substance to 5.0 mu g/ml by using a mobile phase to serve as a reference substance solution. The results are shown in Table 2.
TABLE 2 blood drug levels at different times after gastric gavage in mice
The experimental results show that the serum drug concentration of the sample a (namely the crystal form A) mouse after gastric lavage administration is higher, which indicates that the sample a has better bioavailability.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. Crystalline form a of the compound trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2, the compound represented by the formula:
the crystalline form is characterized by a single crystal X-ray diffraction pattern as shown in figure 2.
2. Form A according to claim 1, having a differential scanning calorimetry pattern with an endotherm at 161.8 ℃.
3. A process for the preparation of form a according to any one of claims 1 to 2, characterized in that: dissolving trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 in a good solvent to prepare a near saturated solution, slowly volatilizing the solution under natural conditions for crystallization or slowly cooling the near saturated solution at 50 ℃ to 0-5 ℃ at the speed of 0.1-0.5 ℃/min for crystallization, collecting crystals and drying to prepare the trans-4-phenyl-5-o-chlorobenzyl pyrrolidone-2 crystal form A.
4. A process for the preparation of form a according to claim 3, characterized in that: the good solvent is one or more of methanol, ethanol, acetone, chloroform, ethyl acetate, acetonitrile, ethyl formate, tetrahydrofuran, 1, 4-dioxane, diethyl ether, n-heptane, isopropylamine, methyl isobutyl ketone, acetic acid isopropanol, methyl tert-butyl ether, toluene and 2-methyltetrahydrofuran.
5. The use of the crystal form a as claimed in any one of claims 1 to 2 for the preparation of highly selective calcium antagonists, improving cerebral dysfunctions, senile dementia, anti-depression, learning and memory enhancing drugs.
6. A pharmaceutical composition comprising the crystalline form a of any one of claims 1 to 2 and a pharmaceutically acceptable carrier.
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| CN1040747C (en) * | 1994-05-07 | 1998-11-18 | 中国科学院昆明植物研究所 | N-substituting group-4-substituted benzyl-5-alkyl-5-substituted benzyl-pyrrolidone-2, and its intermediate, its synthetic method and its appliance |
| CN1156444C (en) * | 2002-07-04 | 2004-07-07 | 中国科学院昆明植物研究所 | Optical breaking process of d1-trans-4-phenyl-5-O-chlorobenzyl pyrrolidone-2 |
| CN103877080B (en) * | 2013-03-13 | 2016-01-27 | 贵州省中国科学院天然产物化学重点实验室 | 4,5-bis-replaces-medicinal usage of 2-Pyrrolidone compound |
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