CN110950835A - Stable lugol pure compounds - Google Patents
Stable lugol pure compounds Download PDFInfo
- Publication number
- CN110950835A CN110950835A CN201811131310.1A CN201811131310A CN110950835A CN 110950835 A CN110950835 A CN 110950835A CN 201811131310 A CN201811131310 A CN 201811131310A CN 110950835 A CN110950835 A CN 110950835A
- Authority
- CN
- China
- Prior art keywords
- hydrate
- composition
- water
- luggezin
- temperature
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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 the technical field of medicines, and particularly relates to a luggezin monohydrate compound, which contains a crystal water and has the advantages that: high purity, good stability, and no obvious moisture absorption weight gain even under high humidity condition.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a Rungel hydrate and a preparation method thereof.
Background
Luggezin (Luseogliflozin) is a new SGLT-2 inhibitor drug approved for the treatment of type 2 diabetes in 2014.
The structural formula is as follows:
lugelliflozin structural formula
Through the research on luggezin, the inventor of the invention discloses a novel luggezin hydrate crystal, which has the advantages that: the purity is high, and the maximum impurity is less than 1 per thousand; good stability, and no obvious moisture absorption weight gain even under high humidity condition.
Disclosure of Invention
One object of the present invention is to disclose a luogliflozin monohydrate.
In another object of the invention, a process for the preparation of luggezin monohydrate is disclosed.
In yet another object of the present invention, a pharmaceutical composition comprising luogliflozin monohydrate is disclosed.
The present disclosure will now be described in detail for the purpose of the invention.
The invention provides a Rungelne monohydrate (shown as a formula I),
（Ⅰ）
the Karl Fischer method is the most specific and accurate method for measuring water in various chemical methods for measuring water in substances, is listed as a standard method for measuring water in many substances, and is particularly an organic compound, and the result is reliable. Said inventive compounds contained between 3.12% and 4.89% moisture by weight, measured in 6 batches. The theoretical content of water in the luggezin sesquihydrate is 3.98%, and the compound provided by the invention can be determined to contain a crystal water.
The Rungelning monohydrate crystal is measured by a D/Max-2500.9161 type X-ray diffractometer under the following measuring conditions: cu Ka target, tube voltage 40KV, tube current 100 mA. The characteristic absorption peaks (2. theta.) and D values of X-ray powder diffraction were as follows.
The 2 theta value is measured with a light source with an accuracy of + -0.2 deg. in the present invention, and therefore represents that the above-mentioned value is allowed to have a reasonable error range of + -0.2 deg..
And (3) melting point determination: the melting point was measured according to the first method of appendix VI C of the pharmacopoeia of the people's republic of China (2010 edition, two parts), and the measured melting point was 159.4 ℃ -160.5 ℃.
The invention also discloses a preparation method of the lugelliflozin hydrate crystal, which is obtained by heating and dissolving lugelliflozin in an acetone-water solution, naturally cooling to room temperature, and then preserving the temperature for a period of time.
The method specifically comprises the following steps: luggezin added 4-5 times (weight-volume ratio) acetone-water = 7-5: 2-1, heating to 70-75 ℃, filtering while hot, naturally cooling the filtrate to room temperature, preserving the temperature for 5-10 hours, precipitating crystals, filtering, and drying to obtain the product.
The used lugolagliflozin is readily available commercially.
It is a further object of the present invention to provide a composition comprising luoglabric hydrate crystals in combination with one or more pharmaceutically acceptable carriers.
The pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. The composition can be used for preparing oral preparation and injection.
The amount of active ingredient (compound of the invention) contained in the pharmaceutical composition and unit dosage form may be varied widely depending upon the condition of the patient and the condition to be diagnosed by the physician, and the amount or concentration of the compound employed may vary widely from 1% to 40% by weight of the composition.
The invention also provides the application of the luggezin hydrate in the preparation of the medicine for treating diabetes.
Stability test
The inventor researches the chemical stability of the crystal form of the invention, and the investigation conditions are high temperature (60 +/-2 ℃), strong light irradiation (4500 Lx +/-500 Lx) and high humidity (92.5 percent, RH) investigation indexes are appearance, content and related substances.
As a result: under the conditions of strong light, high temperature and high humidity, the appearance, related substances and contents are not changed, which shows that the chemical stability is good, and the method is suitable for the preparation and long-term storage of the pharmaceutical preparation.
Determination of the water content in the hydrate crystals according to the invention at 40 ℃ under different Relative Humidity (RH) conditions (75%, 92.5%):
as a result: at 40 ℃, under different Relative Humidity (RH) conditions (75%, 92.5%), the moisture remained constant, indicating good stability, suitable for the manufacture and long-term storage of pharmaceutical formulations.
Determination of moisture in ruxagliflozin at 40 ℃, under different Relative Humidity (RH) conditions (75%, 92.5%):
as a result: under the condition of 40 ℃ and different Relative Humidity (RH) (75%, 92.5%), lugellifuge has hygroscopic weight increment and instability to humidity.
The specific implementation mode is as follows:
the present invention is further described below with reference to examples to enable those skilled in the art to better understand the present invention. The examples are illustrative only and are not meant to limit the scope of the invention in any way.
The Rungegliflozin used in the invention is obtained from a commercial way, has the purity of 99.1 percent (HPLC normalization method), and the chemical structure of the Rungegliflozin is verified to be correct by nuclear magnetic resonance hydrogen spectrum and element analysis.
The water content measured by the Karl Fischer method was 0.22%.
Example 1
200 g of kruegliflozin and 1000ml of acetone-water (5: 2) mixed solution are added into a 2000ml reaction bottle provided with a stirrer, a thermometer and a condenser, stirring is started, heating is carried out until the temperature is raised to 70-75 ℃, and the mixture is completely dissolved and filtered while the mixture is hot. Naturally cooling the filtrate to room temperature, preserving the heat for 8 hours, separating out crystals, filtering, and drying indoors to obtain 181.6 g of lugelliflozin white crystals, the melting point of which is 183.1-184.6 ℃, and the content of which is 99.86%. The water content was 3.98% by weight as determined by the Karl Fischer method.
Instrument type and measurement conditions: japan science D/max 2500 type diffractometer; CuKa 40Kv 100mA, 2 theta scanning range: 0-50°。
The compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. The composition can be used for preparing oral preparation and injection. Which are given by way of illustration only and are not meant to limit the scope of the invention in any way.
Example 2
Tablet containing luggezin monohydrate
Prescription: 80 g of luggezin monohydrate, 210 g of lactose, 25 g of PEG-4000, 6 g of magnesium stearate, 30 g of povidone K30, 33 g of croscarmellose sodium and a proper amount of distilled water, and the luggezin monohydrate, the lactose and the PEG-4000 are prepared into 1000 tablets.
The process comprises the following steps: pulverizing PEG-4000 and lugelizine monohydrate together, sieving with 80 mesh sieve, mixing with other materials, making soft material with distilled water, granulating with 16 mesh sieve, drying at 40-45 deg.C in drying oven, grading with 16 mesh sieve, adding magnesium stearate into the dried granules, mixing, and tabletting.
Claims (6)
1. A Rungel pure compound of formula I,
（Ⅰ）
said hydrate containing from 3.12% to 4.89% by weight of water as determined by the Karl Fischer method;
the crystal of the lugger hydrate has the following 2 theta diffraction angle and D value in CuKa ray as characteristic X-ray powder determination,
the error of the 2 θ diffraction angle was ± 0.2.
2. The process for the preparation of crystalline luxagliflozin hydrate according to claim 1, which is obtained by dissolving luxagliflozin in an acetone-water solution by heating, naturally cooling to room temperature, and keeping the temperature for a period of time.
3. A method according to claim 2, characterized by comprising the steps of: lugolay neat add 4-5 times weight/volume ratio acetone-water = 7-5: 2-1, heating to 70-75 ℃, filtering while hot, naturally cooling the filtrate to room temperature, preserving the temperature for 5-10 hours, precipitating crystals, filtering, and drying to obtain the product.
4. A composition comprising the lugger hydrate crystal of claim 1 and one or more pharmaceutically acceptable carriers.
5. The ruoglipta hydrate composition as claimed in claim 4, wherein the composition is used for preparing oral preparation.
6. Use of the luggezin hydrate of claim 1 in the manufacture of a medicament for the treatment of diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811131310.1A CN110950835A (en) | 2018-09-27 | 2018-09-27 | Stable lugol pure compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811131310.1A CN110950835A (en) | 2018-09-27 | 2018-09-27 | Stable lugol pure compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110950835A true CN110950835A (en) | 2020-04-03 |
Family
ID=69968022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811131310.1A Pending CN110950835A (en) | 2018-09-27 | 2018-09-27 | Stable lugol pure compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110950835A (en) |
-
2018
- 2018-09-27 CN CN201811131310.1A patent/CN110950835A/en active Pending
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Legal Events
| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200403 |
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| WD01 | Invention patent application deemed withdrawn after publication |