CN106543124A - dapagliflozin compound - Google Patents
dapagliflozin compound Download PDFInfo
- Publication number
- CN106543124A CN106543124A CN201510596304.3A CN201510596304A CN106543124A CN 106543124 A CN106543124 A CN 106543124A CN 201510596304 A CN201510596304 A CN 201510596304A CN 106543124 A CN106543124 A CN 106543124A
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- CN
- China
- Prior art keywords
- dapagliflozin
- incubated
- composition
- crystal
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/10—Oxygen atoms
-
- 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 belongs to pharmaceutical technology field, and in particular to the Dapagliflozin compound of stable crystal form, the invention further relates to contain the preparation method of the Dapagliflozin of above-mentioned crystal formation.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to crystal of Dapagliflozin and preparation method thereof.
Background technology
Dapagliflozin is a kind of white 2 inhibitor of sodium glucose co-transporter 2, FDA (Food and Drug Adminstration) (FDA) was announced on January 8th, 2014, ratify Dapagliflozin is used for the treatment of diabetes B, while require that manufacturer carries out with regard to medicine relevant risk study after listing.Dapagliflozin trade name Farxiga, is researched and developed by Bristol Myers Squibb.
The structural formula of Dapagliflozin is as follows：
Dapagliflozin structural formula
Dapagliflozin has various preparation methods, and because its process for purification is different, purity is also different.In research process, the method for repeating document, the Dapagliflozin that the present invention is obtained have the advantage that：Purity is high, and maximum contaminant is less than 1 ‰；Good stability to light；Toxicity is low.
The content of the invention
One object of the present invention, discloses a kind of crystal of Dapagliflozin.
Another object of the present invention, discloses the preparation method of Dapagliflozin crystal.
A further object of the present invention, discloses the pharmaceutical composition comprising Dapagliflozin crystal.
The invention also discloses application of the Dapagliflozin crystal in the medicine of manufacture treatment diabetes.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of Dapagliflozin（Shown in formula I）Crystal,
The Dapagliflozin crystal, is determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values,
In the present invention, the measure of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational error range, and its error range is ± 0.2 °.
Another object of the present invention, discloses the preparation method of Dapagliflozin crystal.
Document report, Dapagliflozin have various preparation methods, and because its process for purification is different, purity is also different.In research process, repeat the Dapagliflozin crystallization that the method for document is obtained, to light less stable.The present inventor explores the relation of refining solvent and the Dapagliflozin crystal for obtaining by substantial amounts of experiment, by by Dapagliflozin in acetone-water solution heating for dissolving, naturally cool to room temperature, then be incubated the Dapagliflozin crystal that a period of time obtains the present invention.
The preparation method of the Dapagliflozin crystal of the present invention, it is characterised in that comprise the following steps：Dapagliflozin adds 6-7 times（Weight or measurement (WM) ratio）Acetone-water=6：In 4 mixed liquor, 65 DEG C -68 DEG C are heated to, are incubated 40 minutes, filter while hot, naturally cool to room temperature, then be incubated 3-4 hours, separate out crystallization, filtered, drying obtains the above-mentioned Dapagliflozin crystal of high-purity.
The method is reproducible, is amplified to pilot-scale, and content and crystal formation can reappear very well.
Dapagliflozin used, according to the method synthesis that document is provided, the chemical constitution Jing nuclear magnetic resoance spectrum of the Dapagliflozin of synthesis, elementary analysis prove that chemical constitution is correct.
A further object of the present invention, there is provided the composition comprising Dapagliflozin crystal and the Dapagliflozin of one or more pharmaceutically acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, crystal of the present invention is combined with acceptable liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare injection.
The active ingredient contained in pharmaceutical composition and unit dosage form（Crystal of the present invention）Amount can be specifically applied according to the situation of the state of an illness of patient, diagnosis, the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is the 1%～30% of composition（Weight）.
Present invention also offers application of the Dapagliflozin crystal in the medicine of manufacture treatment diabetes.
Stability test
Inventor is studied to the chemical stability of crystal formation of the present invention, strong illumination（4500Lx±500lx）, inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under intense light conditions, outward appearance, relevant material, content do not change, and illustrate that chemical stability is good, are adapted to the manufacture and long term storage of pharmaceutical preparation.
Under the conditions of same light is shone, the stability of the Dapagliflozin that document is obtained：
Specific embodiment：
With reference to embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from the present invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
1
Equipped with stirring, thermometer, in the 1000ml reaction bulbs of condenser, the acetone-water of 100 grams of Dapagliflozins of addition and 650ml -=6：4 mixed liquor, starts stirring, is heated to 65 DEG C -68 DEG C, treats all molten clear, is incubated 40 minutes, filters while hot.Filtrate naturally cools to room temperature, then is incubated 3-4 hours, separates out crystallization, filters, and drying obtains final product the above-mentioned Dapagliflozin crystal of high-purity, and content 100.1%, dissolvent residual detection meet the requirements.
The X-ray diffraction instrument model of the crystallization and condition determination：2500 type diffractometers of Rigaku D/max； CuKa
40Kv 100mA;2 θ sweep limits：0-50°。
Embodiment 2
Tablet containing Dapagliflozin crystal formation
Prescription：5 grams of Dapagliflozin crystal formation, 650 grams of lactose, 80 grams of PVPP, 50 grams of PEG-4000,88 grams of hydroxypropyl methyl cellulose distill appropriate amount of water, and magnesium stearate 5g makes 1000.
Technique：PEG-4000 is crushed jointly with Dapagliflozin, crosses 80 mesh sieves, with distilled water softwood, granulation, low temperature drying, compressing tablet after mixing with other materials.
Claims (6)
1. formula（Ⅰ）Dapagliflozin compound,
（Ⅰ）
It is characterized in that：In being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction and relative intensity,
The error of the 2 θ angles of diffraction is 0.2.
2. the preparation method of Dapagliflozin crystal described in claim 1, by by Dapagliflozin in acetone-water solution heating for dissolving, naturally cool to room temperature, then be incubated a period of time and obtain.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Dapagliflozin 6-7 times of acetone-water of addition -=6：In 4 mixed liquor, 65 DEG C -68 DEG C are heated to, are incubated 40 minutes, filter while hot, naturally cool to room temperature, then be incubated 3-4 hours, separate out crystallization, filtered, drying is obtained.
4. a kind of composition containing Dapagliflozin crystal described in claim 1 and one or more pharmaceutically acceptable carrier composition.
5. 4 required by right described in composition, it is characterised in that said composition be used for prepare oral solid formulation.
6. application of the Dapagliflozin described in claim 1 in the medicine of manufacture treatment diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510596304.3A CN106543124A (en) | 2015-09-18 | 2015-09-18 | dapagliflozin compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510596304.3A CN106543124A (en) | 2015-09-18 | 2015-09-18 | dapagliflozin compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106543124A true CN106543124A (en) | 2017-03-29 |
Family
ID=58363030
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510596304.3A Pending CN106543124A (en) | 2015-09-18 | 2015-09-18 | dapagliflozin compound |
Country Status (1)
| Country | Link |
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| CN (1) | CN106543124A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107714667A (en) * | 2017-11-20 | 2018-02-23 | 威海贯标信息科技有限公司 | A kind of Dapagliflozin agent composition |
| CN108699020A (en) * | 2016-05-24 | 2018-10-23 | 江苏豪森药业集团有限公司 | Dapagliflozin novel crystal forms and its preparation method and application |
| CN111559997A (en) * | 2019-02-13 | 2020-08-21 | 罗欣药业(上海)有限公司 | Novel dapagliflozin crystal form and preparation method thereof |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
-
2015
- 2015-09-18 CN CN201510596304.3A patent/CN106543124A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108699020A (en) * | 2016-05-24 | 2018-10-23 | 江苏豪森药业集团有限公司 | Dapagliflozin novel crystal forms and its preparation method and application |
| CN108699020B (en) * | 2016-05-24 | 2021-10-15 | 江苏豪森药业集团有限公司 | Novel dapagliflozin crystal form and preparation method and application thereof |
| CN107714667A (en) * | 2017-11-20 | 2018-02-23 | 威海贯标信息科技有限公司 | A kind of Dapagliflozin agent composition |
| CN111559997A (en) * | 2019-02-13 | 2020-08-21 | 罗欣药业(上海)有限公司 | Novel dapagliflozin crystal form and preparation method thereof |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
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| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
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Application publication date: 20170329 |