CN107344924A - A kind of butyrate clevidipine dihydrate compound - Google Patents
A kind of butyrate clevidipine dihydrate compound Download PDFInfo
- Publication number
- CN107344924A CN107344924A CN201610284814.1A CN201610284814A CN107344924A CN 107344924 A CN107344924 A CN 107344924A CN 201610284814 A CN201610284814 A CN 201610284814A CN 107344924 A CN107344924 A CN 107344924A
- Authority
- CN
- China
- Prior art keywords
- dihydrate
- butyrate clevidipine
- composition
- clevidipine
- butyrate
- 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
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The present invention relates to a kind of new butyrate clevidipine hydrate and preparation method thereof, the hydrate contains two crystallizations water, has purity high, maximum contaminant is less than 1 ‰；Stability is good, even if the weightening of moisture absorption under high humidity conditions also unobvious.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to butyrate clevidipine dihydrate and preparation method thereof, the present invention is also
It is directed to use with the application of the composition resisting cardiovascular disease of this dihydrate.
Background technology
Hypertension is the most common chronic disease in China, and the most important hazards of cardiovascular and cerebrovascular diseases.Blood pressure is elevated
Major complications have cerebral apoplexy, myocardial infarction, heart failure and CKD etc., not only disable, fatal rate height, and seriously
Consumption medical treatment and social resources, heavy burden is caused to family and country.It is in these years both domestic and external it was verified that hypertension is
The disease that can prevent and control, the blood pressure level of hyperpietic is reduced, can obviously reduce cerebral apoplexy and the events of heart attack, shown
Writing improves the life quality of patient, effectively reduces Disease Spectrum.
Butyrate clevidipine is the new short-acting dihydropyridine calcium channel antagonist developed by Medicines companies,
In August, 2008 lists in the U.S. first, trade name Cleviprex.This product is emulsion for injection, unsuitable oral or oral for treating
Invalid hypertension, it can also be used to treat the rise of surgical site infections acute blood pressure.
Butyrate clevidipine has great advantage in validity and security, but in actual production process, applicant
It was found that existing in butyrate clevidipine preparation technology, purification difficult, impurity content be higher, crystal formation by patent protection and has certain
The problems such as moisture absorption is increased weight.The butyrate clevidipine dihydrochloride dihydrate crystal that the present inventor obtains on the basis of many experiments, has
The advantages of：Purity is high, and maximum contaminant is less than 1 ‰；Stability is good, even if the weightening of moisture absorption under high humidity conditions also unobvious.
The content of the invention
One object of the present invention, disclose a kind of butyrate clevidipine dihydrate.
Another object of the present invention, disclose the preparation method of butyrate clevidipine dihydrate.
A further object of the present invention, disclose the pharmaceutical composition for including butyrate clevidipine dihydrate.
Applied the invention also discloses butyrate clevidipine dihydrate in the medicine for preparing resisting cardiovascular disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of butyrate clevidipine dihydrate（Shown in formula I）,
（Formulas I）
Karl_Fischer method（Karl Fischer methods）Be it is a kind of determine material in moisture all kinds of chemical methodes in, it is the most special to water
First, method the most accurate, has been listed in the standard method of determination of moisture in many materials, especially organic compound, as a result
Reliably.
Determined through 10 batches, the moisture that described invention compound contains 6.78%-8.23% (percentage by weight) it
Between.The theoretical content of butyrate clevidipine dihydrate reclaimed water is 7.31%, it can be assumed that invention compound is dihydrate.
The butyrate clevidipine dihydrochloride dihydrate crystal, determined using D/Max-2500.9161 types x-ray diffractometer, measure
Condition：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）, D values and relative intensity
It is as follows,
The measure of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow have certain conjunction
The error range of reason, its error range are ± 0.2 °.
Another object of the present invention, disclose the preparation method of butyrate clevidipine dihydrochloride dihydrate crystal, pass through by
Butyrate clevidipine dissolves in chloroform-hexamethylene-heated in water solution, naturally cools to room temperature, then is incubated and obtains for a period of time
Arrive.
Specifically include the following steps：Butyrate clevidipine add 10-13 times of weight or measurement (WM) than chloroform-hexamethylene-
Water=12.3-15.7:6.8-7.5:In 9.2-10.9 mixed liquor, it is heated to dissolving, filtrate naturally cools to 25 DEG C -30 DEG C,
Insulation 18-24 hours are stood again, separate out crystallization, filtering, through being dried to obtain.
Substantial amounts of experiment proves：The addition of hexamethylene, the proportioning of mixed liquor, the temperature and time of standing are to obtaining butyric acid of the present invention
Clevidipine dihydrochloride dihydrate crystal is most important.
A further object of the present invention, there is provided include butyrate clevidipine dihydrochloride dihydrate crystal and one or more pharmacy
The composition of the butyrate clevidipine dihydrate of upper acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, make the compounds of this invention and preparation
Acceptable solid or liquid-carrier combine on, and be allowed to arbitrarily with acceptable adjuvant and excipient on galenic pharmacy
With reference to being prepared into particulate or microballoon.Said composition is used to prepare oral formulations.Contain in pharmaceutical composition and unit dosage form
Active ingredient（The compounds of this invention）Amount can be specifically applied according to the state of an illness, the situation of diagnosis of patient, institute
The amount or concentration of compound are adjusted in a wider scope, the amount scope of reactive compound for composition 1%~
30%（Weight）.
Present invention also offers application of the butyrate clevidipine dihydrate in resisting cardiovascular disease.
Stability test
Inventor is studied the chemical stability of the crystal formation of the present invention, and investigation condition is high temperature（60℃ ±2℃）, it is strong
Light irradiation（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under strong light, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, explanation
Chemical stability is good, is adapted to the manufacture of pharmaceutical preparation and long-term storage.
Embodiment：
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this hair
It is bright.Embodiment is only explanatory, is in no way intended to the scope that it limit the invention in any way.
Embodiment 1
Equipped with stirring, thermometer, condenser 1L reactors in, add 61.8 grams of butyrate clevidipines and 270ml chloroforms,
138ml hexamethylenes, 210ml water, it is heated to dissolving, filtrate naturally cools to 25 DEG C -30 DEG C, then stands insulation 18-24 hours, analysis
Go out crystallization, filtering, through indoor seasoning, obtain 54.9 grams of butyrate clevidipine dihydrate white crystals, content 99.96% is single
One impurity is less than 0.04%.Determined through thermogravimetry, the moisture containing 7.01% (percentage by weight).
Using standard and conventional technique, make the compounds of this invention and acceptable solid or liquid-carrier knot on galenic pharmacy
Close, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.The combination
Thing is used to prepare oral formulations, injection.Only citing is illustrated, and is in no way intended to the model that it limit the invention in any way
Enclose.
Embodiment 2
Tablet containing butyrate clevidipine dihydrate
Prescription：4 grams, microcrystalline cellulose 80g, lactose 120g of butyrate clevidipine dihydrate, carboxyrnethyl starch sodium 10g, 2.8 grams
PEG-4000,1 gram of magnesium stearate, 17 grams of Ac-Di-Sol, appropriate amount of water is distilled, is made 1000.
Claims (6)
1. the dihydrate of butyrate clevidipine shown in formula I,
（Ⅰ）
Determined with DTG, the dihydrate contains percentage by weight 6.78%-8.23% moisture；The butyric acid chlorine dimension ground
The crystal of flat dihydrate, in being determined by the use of CuKa rays as characteristic X-ray powder, its collection of illustrative plates has the following 2 θ angles of diffraction, brilliant
Interplanar distance (d values) and relative intensity（I/I0）,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of butyrate clevidipine dihydrochloride dihydrate crystal described in claim 1, by by butyrate clevidipine in chlorine
Imitative-hexamethylene-heated in water solution dissolving, naturally cools to room temperature, then be incubated and obtain for a period of time.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Butyrate clevidipine adds 10-13 times and weighed
Chloroform-hexamethylene-water=12.3-15.7 of amount-volume ratio:6.8-7.5:9.2-10.9 mixed liquor in, be heated to molten
Solution, filtrate naturally cool to 25 DEG C -30 DEG C, then stand insulation 18-24 hours, separate out crystallization, filtering, through being dried to obtain.
4. a kind of butyrate clevidipine dihydrochloride dihydrate crystal containing described in claim 1 and one or more are pharmaceutically acceptable
Carrier composition butyrate clevidipine dihydrate composition.
5. the composition of the butyrate clevidipine dihydrate described in claim 4, it is characterised in that said composition is used to prepare
Oral formulations.
6. butyrate clevidipine dihydrate described in claim 1 is in the middle application of resisting cardiovascular disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610284814.1A CN107344924A (en) | 2016-05-04 | 2016-05-04 | A kind of butyrate clevidipine dihydrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610284814.1A CN107344924A (en) | 2016-05-04 | 2016-05-04 | A kind of butyrate clevidipine dihydrate compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107344924A true CN107344924A (en) | 2017-11-14 |
Family
ID=60253105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610284814.1A Pending CN107344924A (en) | 2016-05-04 | 2016-05-04 | A kind of butyrate clevidipine dihydrate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107344924A (en) |
-
2016
- 2016-05-04 CN CN201610284814.1A patent/CN107344924A/en active Pending
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171114 |
|
| WD01 | Invention patent application deemed withdrawn after publication |