CN107674031A - A kind of dexmedetomidine hydrochloride crystal - Google Patents
A kind of dexmedetomidine hydrochloride crystal Download PDFInfo
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- CN107674031A CN107674031A CN201610623751.8A CN201610623751A CN107674031A CN 107674031 A CN107674031 A CN 107674031A CN 201610623751 A CN201610623751 A CN 201610623751A CN 107674031 A CN107674031 A CN 107674031A
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- dexmedetomidine hydrochloride
- crystal
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- dexmedetomidine
- ethyl alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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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
- C07B2200/07—Optical 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, specifically, is related to a kind of dexmedetomidine hydrochloride crystal.Wherein, described dexmedetomidine hydrochloride crystal chemistry structural formula is as follows：
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, is related to a kind of dexmedetomidine hydrochloride crystal.
Background technology
Dexmedetomidine hydrochloride：
Chemistry is entitled：(+) -4- (S)-[1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazole hydrochlorides
Structural formula is：
Dexmedetomidine hydrochloride is α 2- adrenoceptor agonists, clinically suitable for being opened during intensive care
The intubation that begins and the calmness using lung ventilator patient.Pass through exciting presynaptic membrane alpha-2 receptor, it is suppressed that the release of norepinephrine,
And terminate the conduction of pain signal；By exciting postsynaptic membrane acceptor, Dexmedetomidine inhibit sympathetic activity so as to
Cause the decline of blood pressure and heart rate；When generation analgesic activity is combined with the alpha-2 receptor in spinal cord, calm and anxiolytic can be caused.
This product can also reduce the dosage of anesthetic, improve hemodynamic stability in operation and reduce myocardial ischaemia
Incidence.This product listing formulation is injection, multiple studies have shown that existing dexmedetomidine hydrochloride crystal and injection are to height
Temperature, strong acid, highly basic equistability are preferable, only poor to light durability.
Intravenously administrable is one of important channel of drug therapy, because it is rapid-action, be used widely bioavilability is high.
Mostly in clinical practice is that injection is added in transfusion and combines intravenously administrable after compatibility, the particulate matter that triggers therefrom and its
The existing document report of caused adverse reaction.Particulate matter refers to visually observe less than through miillpore filter, microscope and electricity
The observable a large amount of particulates of sub- microscope and crystallite.Larger particulate matter can cause local circulation obstacle, cause blood vessel
Embolism, particulate excessively cause local stoppages and blood supply insufficiency, histanoxia and produce oedema and phlebitis.Particulate matter may be used also
Cause the harm such as allergic reaction, thermal source sample reaction.The source of particulate matter after injection compatibility of drugs, including injection medicine is in itself
Contain or inject that medicine is undissolved, and because the change of solvent separates out some drugses after injection compatibility of drugs, injection medicine is matched somebody with somebody
Occur physically or chemically to change after 5, produce particulate matter etc..
In the production process of medicine, drying condition, cooling condition and recrystallization condition may cause drug crystal forms
Transformation, and drug crystal forms have an impact to the bioavilability of medicine, action time and toxic side effect
Application No. CN201610051814.7 Chinese patent discloses a kind of dexmedetomidine hydrochloride crystal formation C, the crystalline substance
Type C with the X-ray powder diffraction spectrogram that the 2 θ ± 0.2 ° angles of diffraction represent 7.511,11.983,12.622,16.307,
17.597th, characteristic peak is shown at 24.084.
In view of this, it is special to propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of new crystal of dexmedetomidine hydrochloride.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of dexmedetomidine hydrochloride crystal, chemical structural formula are as follows：
The characteristic peak of the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurements 2 θ be 10.1 °, 14.9 °,
Shown at 18.0 °, 20.3 °, 26.8 °, 29.8 °, 30.5 °.
The existing dexmedetomidine hydrochloride crystal of in the market and injection are preferable to high temperature, strong acid, highly basic equistability,
It is only poor to light durability.Tested by series of stable, dexmedetomidine hydrochloride crystal produced by the present invention compared with
Crystal is the same, there is preferable stability, difference to high temperature, strong acid, highly basic, and crystal produced by the present invention still has to illumination
Preferable stability.
The present inventor is also using dexmedetomidine hydrochloride crystal obtained by the present invention as raw material, by the preparation technology of injection,
Corresponding dexmedetomidine hydrochloride parenteral solution has been made.By a series of experiments, the present inventor surprisingly has found, obtained hydrochloric acid
Particulate matter is less after Dexmedetomidine parenteral solution compatibility, and its particulate matter remains to comply fully with after placement 4h《China
Pharmacopeia》The regulation of version in 2010, in addition, obtained dexmedetomidine hydrochloride parenteral solution also have more preferable drug effect.
The present invention also provides the preparation method of the dexmedetomidine hydrochloride crystal simultaneously.This method includes following step
Suddenly：
(1) dexmedetomidine hydrochloride dissolving crude product is carried out while stirring in ethyl acetate and absolute ethyl alcohol mixed solvent
Heating water bath；
(2) charcoal absorption is added into resulting solution, is filtered while hot；
(3) by the filtrate cooling and standings of collection, separated out to crystallization；
(4) gained crystallization is dried in vacuo after being washed with absolute ethyl alcohol, produces dexmedetomidine hydrochloride crystal.
The dosage of ethyl acetate/absolute ethyl alcohol described in step (1) is the 8~10 of dexmedetomidine hydrochloride crude product weight
Times, dosage here is volume, and weight is quality, i.e., volume is the multiple of weight, and unit is L/kg or mL/g.
Described ethyl acetate and the volume ratio of absolute ethyl alcohol in the mixed solvent ethyl acetate and absolute ethyl alcohol are 1:3~5.
Described bath temperature is 70~80 DEG C.
Dwell temperature described in step (3) is 45~55 DEG C.
Described time of repose is 2~4 hours.
Drying temperature described in step (4) is 25~30 DEG C.
Compared to the prior art, dexmedetomidine hydrochloride crystal of the invention has preferable stability, using the crystal as original
Particulate matter is less after dexmedetomidine hydrochloride parenteral solution compatibility made from material, and its particulate matter has remained to after placement 4h
Meet entirely《Chinese Pharmacopoeia》The regulation of version in 2010, in addition, obtained dexmedetomidine hydrochloride parenteral solution also have more preferable
Drug effect.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction pattern of the dexmedetomidine hydrochloride crystal of the present invention；
Fig. 2 is the obtained crystal A during dexmedetomidine hydrochloride crystal C is prepared according to CN105481774A method
X-ray powder diffraction pattern；
Fig. 3 is the obtained crystal C during dexmedetomidine hydrochloride crystal C is prepared according to CN105481774A method
X-ray powder diffraction pattern.
Embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention
In accompanying drawing, the technical scheme in embodiment is clearly and completely described, following examples be used for illustrate the present invention, but
It is not limited to the scope of the present invention.
Embodiment 1
(1) by 1kg dexmedetomidine hydrochlorides dissolving crude product in 2.0L ethyl acetate and 6.0L absolute ethyl alcohol mixed solvents, side
Heated under 70 DEG C of water-baths on stirring side；
(2) charcoal absorption is added into resulting solution, is filtered while hot；
(3) filtrate of collection is stood into 2h at 45 DEG C, there is crystallization to separate out；
(4) gained crystallization is dried in vacuo after being washed with absolute ethyl alcohol at 25 DEG C, produces dexmedetomidine hydrochloride crystal.
The characteristic peak for the X-ray powder diffraction spectrogram (see Fig. 1) that the crystal is obtained using Cu-K alpha ray measurements is in 2 θ
Shown at 10.1 °, 14.9 °, 18.0 °, 20.3 °, 26.8 °, 29.8 °, 30.5 °.
It is below embodiment 2~5, for operating procedure with embodiment 1, specific process parameter is shown in Table 1
The embodiment 2~5 of table 1
The X-ray powder obtained to dexmedetomidine hydrochloride crystal made from embodiment 2~5 using Cu-K alpha ray measurements
Diffraction spectrogram is similar to Example 1.
Comparative example 1, dexmedetomidine hydrochloride crystal C is prepared according to CN105481774A method
According to document
Characterizationandhygroscopicpropertiesofdexmedetomidinehydrochloride,
AnewdrugsubstanceEuropeanJournalofPharmaceuticalSciences, 1 (1994) 219-225 report
Method, crystal A is drawn, the crystal formation A of Dexmedetomidine hydrochloride is proved through X-ray powder diffraction, as shown in Figure 2.
Take Dexmedetomidine crystal A appropriate, be dissolved into n-hexane (70 DEG C), be configured to saturated solution, be heated to reflux, subtract
Press filtration, revolving remove solvent, 45 DEG C of drying crystal C, Dexmedetomidine hydrochloride are proved through X-ray powder diffraction
Crystal formation C, as shown in Figure 3.
The light durability of test example 1 is tested
Crystal made from the embodiment of the present invention and comparative example 1 is placed in light cupboard under 4500Lx ± 500Lx, illumination 10
My god, sampled in the 5th, 10 day, the outward appearance to sample, relevant material and active constituent content detect respectively, the results are shown in Table 2.
The crystal light durability result of the test of table 2
Crystal outward appearance obtained above is white crystalline powder.
As shown in Table 2, dexmedetomidine hydrochloride crystal produced by the present invention is under illumination condition, relevant material and effectively into
Point content has no significant change, and stability is preferable, and stability is better than dexmedetomidine hydrochloride crystal C.
The accelerated test of test example 2
Appoint and take 2 embodiments with crystal made from comparative example 1 under the conditions of 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%
Constant temperature and humidity state stores 6 months, and in 0,1,2,3, June respectively samples detection, and obtained experimental result is shown in Table 3.
The crystal accelerated test result of table 3
As shown in Table 3, dexmedetomidine hydrochloride crystal produced by the present invention still has preferably under long-time illumination condition
Stability, and stability is still better than dexmedetomidine hydrochloride crystal C.
Test example 3
It is prepared by medicine：
Prescription：Dexmedetomidine hydrochloride (in terms of Dexmedetomidine) 0.2g, sodium chloride 18g, sodium tartrate 0.08g, filling
Penetrate with water to 2000ml, be made 1000.
Preparation method：1) water for injection of recipe quantity 95% is taken, 60 DEG C are cooled the temperature to after boiling；2) turn on agitator,
Recipe quantity sodium chloride is added, stirring makes its dissolving after 5 minutes；Dexmedetomidine hydrochloride is added, stirring makes it completely molten for 10 minutes
Solve and be well mixed；3) 30 DEG C are cooled to again, adds the sodium tartrate of recipe quantity, and stirring makes its dissolving, adds major ingredient amount 3%
(w/w) activated carbon stirring and adsorbing 15 minutes；4) mend and add to the full amount of water for injection, continue to stir lower circulation 15 minutes, with 0.5 μm
After the millipore filter filtering of 0.22 μm of stud pole, detection decoction content and pH value are sampled in sample tap, treats that fluid temperature is maintained at
After 30 DEG C, stop stirring and closing cooling penstock；5) after detection is qualified, through 0.22 μm of millipore filter of the embedding third level, fill
Dress, sealing, sterilize 15 minutes in 121 DEG C；6) lamp inspection, packaging, obtain finished product.
By reagent：Prepared according to above-mentioned prescription and preparation method, wherein dexmedetomidine hydrochloride used is real for the present invention
Apply dexmedetomidine hydrochloride crystal made from example 1.
Comparison medicine：Prepared according to above-mentioned prescription and preparation method, wherein dexmedetomidine hydrochloride used is right for the present invention
Dexmedetomidine hydrochloride crystal C made from ratio 1.
Commercially available dexmedetomidine hydrochloride parenteral solution " Ai Beining " (manufacturer：Hengrui Medicine Co., Ltd., Jiangsu Prov.)
The μ g/ml of concentration 4 must be reached with 0.9% sodium chloride solution dilution before administration, therefore, after investigating by reagent and comparison medicine compatibility
The change of particulate matter, by reagent and comparison medicine are added separately in 100mL0.9% sodium chloride solution, are configured to 4 μ
G/ml solution.The particulate matter of the 0th, 1,2,3,4 hour, the results are shown in Table 4 after investigation compatibility.
The by reagent of table 4 and comparison medicine and the particulate matter after 0.9% sodium chloride solution compatibility
As shown in Table 4, compared with using dexmedetomidine hydrochloride crystal C as the comparison medicine that raw material obtains, it is made with the present invention
The crystal of dexmedetomidine hydrochloride is that the by reagent that raw material obtains and particulate matter after 0.9% sodium chloride solution compatibility are few,
And place 4h particulate matters and still conform to《Chinese Pharmacopoeia》The regulation of version in 2010.
The zoopery of test example 4
1. experimental animal and reagent
Animal：Same batch mouse (cleaning grade) 18~23g of body weight, male and female are regardless of, and 2d makes mouse be familiar with experiment before experiment
Room environmental, drinking-water of freely ingesting.
Reagent：By reagent and comparison medicine are the same as test example 3.
2. experimental procedure
Mouse be divided at random I, II two groups, every group 15, the average weight and sex ratio of each group mouse are similar.Each group
Experiment reagent is first injected intraperitoneally in mouse respectively, using the dosage that Dexmedetomidine is counted as 15 μ g/kg, 5min after be injected intraperitoneally respectively again
The lidocaine of various dose.The ratio between adjacent lidocaine is 0.8.
Specific method is：The 1st mouse subcutaneous injection experiment reagent of each group, 5min pneumoretroperitoneums injection lidocaine, if small
Mouse is fainted from fear, then next mouse lowers a dosage, and next mouse raises a dosage if not fainting from fear.Using Dixon-
Mood methods calculate the medicine median effective dose ED of each group lidocaine50.Convulsions judge index：Animal excitability substantially increases,
Activity strengthens, jumped, running, and is fallen down to the ground because limb spasm position can not balance.
3. statistical procedures
Statistical analysis is carried out using software, P ＜ 0.05 are that difference is statistically significant.
4. result conclusion
I groups：By reagent
II group：Comparison medicine
The experiment reagent of table 5 causes convulsions ED to lidocaine50Influence
Compared with I groups,aP<0.05
As shown in Table 5, the ED of I groups lidocaine50Higher than II group, using dexmedetomidine hydrochloride crystal produced by the present invention as
The by reagent that raw material obtains is better than what is obtained using dexmedetomidine hydrochloride crystal C as raw material in the effect of anticonvulsion, calm aspect
Comparison medicine.
The present invention is described in detail, and its object is to allow those skilled in the art to understand the present invention's
Content is simultaneously carried out, and it is not intended to limit the scope of the present invention, what all Spirit Essences according to the present invention were done etc.
Effect change or modification, should all cover within the scope of the present invention.
Claims (8)
1. a kind of dexmedetomidine hydrochloride crystal, it is characterised in that the dexmedetomidine hydrochloride crystal chemistry structural formula is as follows：
The characteristic peak of the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurements 2 θ be 10.1 °, 14.9 °, 18.0 °,
20.3 °, 26.8 °, 29.8 °, show at 30.5 °.
A kind of 2. preparation method of the dexmedetomidine hydrochloride crystal described in claim 1, it is characterised in that described preparation side
Method comprises the following steps：
(1) by dexmedetomidine hydrochloride dissolving crude product in ethyl acetate and absolute ethyl alcohol mixed solvent, heating water bath while stirring；
(2) charcoal absorption is added into resulting solution, is filtered while hot；
(3) by the filtrate cooling and standings of collection, separated out to there is crystallization；
(4) gained crystallization is dried in vacuo after being washed with absolute ethyl alcohol, produces the right U.S. support miaow crystal of hydrochloric acid.
3. preparation method according to claim 2, it is characterised in that ethyl acetate/absolute ethyl alcohol described in step (1)
Dosage be 8~10 times of dexmedetomidine hydrochloride crude product weight, dosage here is volume, and weight is quality, i.e. volume is
The multiple of weight, unit are L/kg or mL/g.
4. preparation method according to claim 2, it is characterised in that described ethyl acetate and absolute ethyl alcohol mixed solvent
The volume ratio of middle ethyl acetate and absolute ethyl alcohol is 1:3~5.
5. preparation method according to claim 2, it is characterised in that the bath temperature described in step (1) is 70~80
℃。
6. preparation method according to claim 2, it is characterised in that the dwell temperature described in step (3) is 45~55
℃。
7. preparation method according to claim 2, it is characterised in that the time of repose described in step (3) is small for 2~4
When.
8. preparation method according to claim 2, it is characterised in that drying temperature described in step (4) is 25~30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610623751.8A CN107674031A (en) | 2016-08-02 | 2016-08-02 | A kind of dexmedetomidine hydrochloride crystal |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610623751.8A CN107674031A (en) | 2016-08-02 | 2016-08-02 | A kind of dexmedetomidine hydrochloride crystal |
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| Publication Number | Publication Date |
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| CN107674031A true CN107674031A (en) | 2018-02-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610623751.8A Pending CN107674031A (en) | 2016-08-02 | 2016-08-02 | A kind of dexmedetomidine hydrochloride crystal |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175339A (en) * | 2015-10-09 | 2015-12-23 | 辰欣药业股份有限公司 | Method for preparing dexmedetomidine hydroch |
| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
-
2016
- 2016-08-02 CN CN201610623751.8A patent/CN107674031A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175339A (en) * | 2015-10-09 | 2015-12-23 | 辰欣药业股份有限公司 | Method for preparing dexmedetomidine hydroch |
| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
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Application publication date: 20180209 |