CN110577507A - Stable cabazitaxel crystal form and preparation method thereof - Google Patents
Stable cabazitaxel crystal form and preparation method thereof Download PDFInfo
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- CN110577507A CN110577507A CN201910653218.XA CN201910653218A CN110577507A CN 110577507 A CN110577507 A CN 110577507A CN 201910653218 A CN201910653218 A CN 201910653218A CN 110577507 A CN110577507 A CN 110577507A
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- C07—ORGANIC CHEMISTRY
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and discloses a stable cabazitaxel crystal form crystallized in a non-aqueous and non-solvent manner and a preparation method thereof. The preparation method of the stable crystal form comprises the steps of dissolving cabazitaxel of any crystal form in chloroalkane, adding or adding into ether or alkane organic solvent, stirring for crystallization, filtering and collecting the product to obtain the product. The stable cabazitaxel crystal form is characterized by X-ray powder diffraction, thermal differential analysis (DSC) and thermogravimetric analysis (TGA), and is different from all disclosed crystal forms. The cabazitaxel crystal form is easy to control solvent residue, stable in long-term storage, simple to prepare, easy to operate, wide in raw material source and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a stable cabazitaxel crystal form, a preparation method and application thereof.
Background
Cabazitaxel, known as Cabazitaxel, having the chemical name 4-acetoxy-2 α -benzoyloxy-5 β, 20-epoxy-1-hydroxy-7 β, 10 β -dimethoxy-9-oxo-11-taxen-13 α -ol- (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate having the following formula (Ӏ):
Cabazitaxel is a microtubule inhibitor that promotes the assembly of microtubule dimers into microtubules by binding to tubulin, stabilizes microtubules by inhibiting microtubule disassembly by preventing the de-polymerization process, and blocks mitosis and interphase cell function of cells, thereby inhibiting mitosis and proliferation of cancer cells. It is used in combination with prednisone to treat patients with metastatic hormone-refractory prostate cancer who have previously been treated with a docetaxel-containing regimen.
The crystal form is one of important factors influencing the quality, the curative effect and the processing performance of a preparation. In recent years, many studies have been made on the crystalline form of cabazitaxel, and these crystalline forms are roughly classified into solvates, hydrates, anhydrates, amorphous forms, and the like. Patent WO2005028462 reports crystalline form a, which is in the form of an acetonide. Subsequently, Chinese patent CN101918385 reports that the crystal form B, C, D, E, F can be converted from the crystal form A under different conditions, wherein an ethanol compound is obtained by aging in ethanol or ethanol/water, an anhydrous solvent-free solvent is obtained by aging in high-temperature desolventizing or oil, and a hydrate is obtained by aging in water. Patent CN103814018A reports crystalline forms C1, C2, C3, C4, C5, C6, C7, C8, C8b, C9 and C9p, the most predominant of which are in the form of solvates of isopropanol, DMSO and acetic acid or in the form of water and solvates. Patent CN104011035A also reports 13 crystal forms, and whether the crystal form is hydrate or solvate is not described in the text, but the crystal form research in the text does not find the kind of the crystal form of the present invention. Patent CN102746258A also reports three crystal forms, among which there are the J crystal form in the form of an ester compound, the G crystal form in the form of a hydrate and the I crystal form not specified. The patent CN103450119A reports the W crystal form and does not indicate whether the W crystal form is a hydrate or solvate crystal form, but the crystal form is researched in comparison with the crystal form in the text, and the crystal form of the invention is not found. In addition, amorphous cabazitaxel crystal form is also reported and studied in patent CN 102659722A.
In summary, in the face of the recent reports of a large number of cabazitaxel crystal forms, a new crystal form cannot be expected to be obtained; secondly, a large number of crystal forms in the prior art are hydrates or solvates, which are at risk of dehydration and desolvation; finally, even though the non-aqueous and non-solvent crystal forms (or whether the crystal forms are hydrates or solvates or not) reported in the prior art are researched by the inventor, the crystal forms also contain a certain amount of crystal water or crystal solvents and even are mixed crystals, and the consistency of the crystal forms among bulk pharmaceutical chemicals is difficult to ensure in practical application, so that the production and the stability of the bulk pharmaceutical chemicals are directly influenced.
Disclosure of Invention
Under the condition that the prior art cannot expect to obtain a new cabazitaxel crystal form, particularly cannot expect to obtain a new cabazitaxel crystal form with good stability, the inventor obtains the new cabazitaxel crystal form by deep ploughing and refining the obtained experience in the field for a long time and relying on certain daily logistics, the stability of the cabazitaxel crystal form is proved to be really good, the dissolution residue is easy to control when the cabazitaxel is used for processing a preparation, the preparation of the cabazitaxel crystal form is easy, the preparation method is beneficial to industrial production, various existing cabazitaxel crystal forms can be used as raw materials for preparing the cabazitaxel crystal form, the cost is saved, and the waste of the defective existing crystal forms is avoided. The technical problem to be solved by the invention is to provide the novel cabazitaxel crystal form.
Specifically, in a first aspect, the present invention provides a cabazitaxel crystal form, wherein a characteristic peak 2 θ of an X-ray powder diffraction pattern of the cabazitaxel crystal form is: 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.6 +/-0.2 degrees, 12.9 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.4 +/-0.2 degrees, 26.1 +/-0.2 degrees and 26.6 +/-0.2 degrees.
Preferably, the characteristic peak 2 theta of the X-ray powder diffraction pattern of the cabazitaxel crystal form of the first aspect of the invention is as follows: 7.2 °, 8.1 °, 9.8 °, 11.1 °, 12.6 °, 12.9 °, 15.3 °, 15.8 °, 16.2 °, 17.1 °, 18.5 °, 19.7 °, 20.4 °, 21.9 °, 22.6 °, 23.9 °, 24.3 °, 25.4 °, 26.1 °, 26.6 °.
accordingly, in a first aspect, the present invention also provides a crystalline cabazitaxel form, characterized in that the crystalline cabazitaxel form has an X-ray powder diffraction pattern substantially as shown in figure 1. Preferably, the cabazitaxel crystal form has an X-ray powder diffraction pattern as shown in figure 1.
Further more preferably, the crystalline form of cabazitaxel of the first aspect of the invention has a thermogram substantially as shown in fig. 2, preferably a thermogram as shown in fig. 2. Fig. 2 shows the crystalline form of cabazitaxel of the first aspect of the invention as a single endothermic peak within 120 ° to 180 °.
Even more preferably, the crystalline form of cabazitaxel of the first aspect of the invention has a thermogravimetric analysis profile substantially as shown in figure 3, preferably as shown in figure 3. Fig. 3 shows that the crystalline form of cabazitaxel of the first aspect of the invention is free of crystal water or solvent.
In a second aspect, the present invention provides a process for the preparation of the crystalline cabazitaxel form of the first aspect of the invention, characterized in that the process comprises the following steps carried out in sequence:
(1) Dissolving cabazitaxel in chloroalkane;
(2) Dropwise adding or stepwise adding an ether organic solvent or an alkane organic solvent into the solution obtained in the step (1); and the combination of (a) and (b),
(3) Collecting white solid precipitated from the solution in the step (2).
preferably, in the preparation method of the second aspect of the present invention, the cabazitaxel in the step (1) is amorphous powder or other arbitrary crystal form.
Also preferably in the production method of the second aspect of the present invention, the chloroalkane in step (1) is dichloromethane.
More preferably, in the preparation method of the second aspect of the present invention, the ratio of the amount of cabazitaxel to dichloromethane is 1 g: 1-20ml, preferably 1 g: 2-7ml, more preferably 1 g: 3-5 ml.
Preferably, in the production process of the second aspect of the present invention, the ethereal organic solvent in the step (2) is methyl t-butyl ether.
Or preferably in the production process of the second aspect of the present invention, the organic solvent of an alkane in the step (2) is n-heptane.
More preferably, in the production process of the second aspect of the present invention, the ratio of the amount of cabazitaxel in step (1) to the amount of methyl tert-butyl ether or n-heptane in step (2) is 1 g: 5-50ml, preferably 1 g: 15-30ml, more preferably 1 g: 20-25 ml.
Preferably, in the production method of the second aspect of the present invention, the collection in step (3) includes filtration, washing and drying. Preferably, the solvent used for washing is an ether-type organic solvent or an alkane-type organic solvent in the step (2). Also preferred is the drying method, wherein the drying is carried out by blowing at 60-100 ℃ for 12-48 hours.
In a third aspect, the present invention provides the use of the crystalline cabazitaxel form of the first aspect of the invention for the long-term stable storage of cabazitaxel. The term "stable" refers to that the cabazitaxel is still in the cabazitaxel raw material medicine quality standard after long-term storage, and no overproof related substances are generated. The storage conditions of the examples can be referred to, but the storage conditions of the drug substances are generally superior to these conditions.
Preferably in the use of the third aspect of the invention, the extended period is from 3 to 36 months, preferably from 12 to 36 months, more preferably from 18 to 36 months, such as 3, 6, 9, 12, 18, 24 or 36 months.
The invention has the advantages that a new cabazitaxel crystal form is obtained, the cabazitaxel crystal form is confirmed to contain no crystallization water or crystallization solvent, the risk of dehydration and solvent removal is not possible, and the solvent residue is easy to control when the cabazitaxel is used for preparation processing; its stability, especially long-term stability, proved to be really good; the preparation process is simple, has no harsh requirements on environment and equipment, is beneficial to industrial production, can utilize various existing cabazitaxel crystal forms as raw materials for preparing the cabazitaxel crystal forms, saves cost and avoids the waste of the existing crystal forms with defects.
For ease of understanding, the present invention incorporates by reference publications which are intended to more clearly describe the invention and which are incorporated herein by reference in their entirety as if fully set forth herein.
The invention will be described in detail below by means of specific embodiments and the accompanying drawings. It is to be expressly understood that the description is illustrative only and is not intended as a definition of the limits of the invention. Many variations and modifications of the present invention will be apparent to those skilled in the art in light of the teachings of this specification.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of the crystalline cabazitaxel form of the present invention.
Fig. 2 is a DSC profile of a crystalline form of cabazitaxel of the present invention.
fig. 3 is a TGA profile of a crystalline form of cabazitaxel of the present invention.
Detailed Description
The present invention will be explained in detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test apparatus used for the experiment:
1, X-ray powder diffraction pattern
The instrument comprises the following steps: full-automatic D/Max-3c X-ray diffractometer for Rigalcu Japan
Ray: Cu/K-alpha 1 (lambda =1.54056)
The scanning mode is as follows: 2 θ = 3-60 °, 0.02/1sec
Voltage: 40 kV and 30 mA
2, thermogram analysis (DSC)
The instrument comprises the following steps: SII Nano, EXSTAR, DSC6220
Temperature rise rate: 10 ℃/min
Temperature range: 60 to 180 DEG C
Carrier gas: high purity nitrogen gas
Thermogravimetric analysis (TGA)
The instrument comprises the following steps: SII Nano, EXSTAR, TG/DTA6200
Temperature rise rate: 10 ℃/min
Temperature range: 22-350 DEG C
Carrier gas: high purity nitrogen gas
Example 1 cabazitaxel amorphous powder 10.0g is weighed, 50mL of dichloromethane is added to the solution to be stirred and dissolved, so that the cabazitaxel amorphous powder is completely dissolved, 250mL of methyl tert-butyl ether is added dropwise to the solution under stirring, a white solid product is separated out in the dropwise adding process, the stirring is carried out for 2 ~ 3h after the dropwise adding is completed, the filtering is carried out, a filter cake is leached by 150mL of methyl tert-butyl ether, a white solid is obtained, the forced air drying is carried out at 80 ℃ for 24h, 9.2g of cabazitaxel white solid product is obtained, the yield is 92%, X-ray powder diffraction, DSC and TGA tests are carried out on the cabazitaxel white solid product, and the corresponding pattern is shown in figures 1-.
Example 2 cabazitaxel amorphous powder 10.0g is weighed and added into dichloromethane 40mL to be stirred and dissolved so as to be completely dissolved and clear, under the stirring condition, the solution is dripped into a reaction bottle containing n-heptane 200mL, white solid products are separated out from the beginning of dripping, after the dripping is completed, the stirring is carried out for 2 ~ 3h, the filtering is carried out, filter cakes are leached by n-heptane 150mL to obtain white solids, air-blast drying is carried out at 80 ℃ for 36h to obtain cabazitaxel white solid products 8.9g, the yield is 89%, and X-ray powder diffraction, DSC and TGA tests are carried out on the cabazitaxel white solid products, which are the same as the preparation of example 1.
Example 3 various cabazitaxel crystal form (or reported crystal form) powders prepared according to the literature of the background art are weighed by 10.0g, and crystallization is carried out according to the method of example 1 or 2, thus obtaining white solid cabazitaxel products with the yield of 86-92%. Each was subjected to X-ray powder diffraction, DSC, and TGA testing, and the crystalline forms prepared from the remaining starting materials were the same as those prepared in example 1, except that they were prepared from a portion of the crystalline form in CN 104011035A.
Example 4 stability studies on the cabazitaxel crystal form of the present invention are performed, and the results are shown in the following table, wherein the cabazitaxel crystal form has excellent stability to temperature, light and humidity, and particularly, after a long-term stability test for 36 months, the quality of the cabazitaxel crystal form is still much higher than the quality standard of cabazitaxel bulk drug.
Claims (9)
1. The cabazitaxel crystal form is characterized in that the characteristic peak 2 theta of an X-ray powder diffraction pattern of the cabazitaxel crystal form is as follows: 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.1 +/-0.2 degrees, 12.6 +/-0.2 degrees, 12.9 +/-0.2 degrees, 15.3 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.4 +/-0.2 degrees, 26.1 +/-0.2 degrees and 26.6 +/-0.2 degrees. Preferably, the characteristic peak 2 theta of the X-ray powder diffraction pattern of the cabazitaxel crystal form is as follows: 7.2 °, 8.1 °, 9.8 °, 11.1 °, 12.6 °, 12.9 °, 15.3 °, 15.8 °, 16.2 °, 17.1 °, 18.5 °, 19.7 °, 20.4 °, 21.9 °, 22.6 °, 23.9 °, 24.3 °, 25.4 °, 26.1 °, 26.6 °.
2. The crystalline cabazitaxel form according to claim 1, wherein the crystalline cabazitaxel form has an X-ray powder diffraction pattern substantially as shown in fig. 1, preferably the crystalline cabazitaxel form has an X-ray powder diffraction pattern as shown in fig. 1.
3. A process for the preparation of a crystalline form of cabazitaxel according to claim 1 or 2, characterized in that the process comprises the following steps carried out in sequence: (a) dissolving cabazitaxel in chloroalkane; (b) dropwise adding or stepwise adding an ether organic solvent or an alkane organic solvent into the solution obtained in the step (a); and (c) collecting the white solid precipitated from the solution in step (b).
4. the method according to claim 3, wherein the cabazitaxel in the step (a) is amorphous powder or other arbitrary crystal form; and/or the chloroalkane in step (a) is dichloromethane.
5. the method according to claim 4, wherein the ratio of cabazitaxel to dichloromethane is 1 g: 1-20ml, preferably 1 g: 2-7ml, more preferably 1 g: 3-5 ml.
6. The method according to claim 3, wherein the ethereal organic solvent in the step (b) is methyl t-butyl ether; alternatively, the alkane organic solvent in step (b) is n-heptane.
7. The process according to claim 6, wherein the ratio of cabazitaxel in step (a) to methyl tert-butyl ether or n-heptane in step (b) is 1 g: 5-50ml, preferably 1 g: 15-30ml, more preferably 1 g: 20-25 ml.
8. The method according to claim 3, wherein the collecting in step (c) comprises filtering, washing and drying, preferably the solvent used for washing is the ether-type organic solvent or the alkane-type organic solvent in step (b), and also preferably the drying is air-drying at 60 ℃ to 100 ℃ for 12 to 48 hours.
9. Use of a crystalline cabazitaxel form according to claim 1 or 2 for long term stable storage of cabazitaxel, wherein the long term is 3 to 36 months, preferably 12 to 36 months, more preferably 18 to 36 months.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011035A (en) * | 2007-01-25 | 2007-08-08 | 新昌县白云草业研究所 | Seashore paspalum young spike isolated culture strain-reproducing technique |
| CN103058960A (en) * | 2012-12-12 | 2013-04-24 | 江苏奥赛康药业股份有限公司 | Cabazitaxel polymorphic form and preparation method thereof |
| CN103333138A (en) * | 2013-07-22 | 2013-10-02 | 北京科莱博医药开发有限责任公司 | Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof |
| US20150141673A1 (en) * | 2013-11-15 | 2015-05-21 | Honghai SONG | Novel crystalline for w of cabazitaxel and method for preparing it |
| CN106674157A (en) * | 2016-12-19 | 2017-05-17 | 扬子江药业集团广州海瑞药业有限公司 | Novel cabazitaxel anhydrous compound and preparation method and crystal form thereof |
-
2019
- 2019-07-19 CN CN201910653218.XA patent/CN110577507A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011035A (en) * | 2007-01-25 | 2007-08-08 | 新昌县白云草业研究所 | Seashore paspalum young spike isolated culture strain-reproducing technique |
| CN103058960A (en) * | 2012-12-12 | 2013-04-24 | 江苏奥赛康药业股份有限公司 | Cabazitaxel polymorphic form and preparation method thereof |
| CN103333138A (en) * | 2013-07-22 | 2013-10-02 | 北京科莱博医药开发有限责任公司 | Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof |
| US20150141673A1 (en) * | 2013-11-15 | 2015-05-21 | Honghai SONG | Novel crystalline for w of cabazitaxel and method for preparing it |
| CN106674157A (en) * | 2016-12-19 | 2017-05-17 | 扬子江药业集团广州海瑞药业有限公司 | Novel cabazitaxel anhydrous compound and preparation method and crystal form thereof |
Non-Patent Citations (1)
| Title |
|---|
| 吕杨 等, 人民卫生出版社 * |
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