CN103450311A - New crystal form of vecuronium bromide, and preparation method and use thereof - Google Patents
New crystal form of vecuronium bromide, and preparation method and use thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 16
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Abstract
The invention discloses a new crystal form I of vecuronium bromide. There are characteristic peaks at 2theta diffraction angles of 5.4+/-0.2DEG, 8.8+/-0.2DEG, 12.4+/-0.2DEG, 13.7+/-0.2DEG, 17.6+/-0.2DEG and 19.7+/-0.2DEG in the X-ray powder diffraction pattern of the crystal form. The invention also discloses a preparation method of the crystal form and a use of the crystal form. The crystal form I of vecuronium bromide improves the dissolvability of vecuronium bromide, is helpful for mitigating or eliminating the untoward effects of blood vessel irritation and ache initiation during injection, reduces the hydroscopic property of vecuronium bromide, substantially enhances the stability of vecuronium bromide, is in favor of the long term storage of a vecuronium bromide raw material and guarantees the product safety through the change of the crystal form structure. The preparation method of the crystal form I of vecuronium bromide has the advantages of simplicity, convenient operation and high yield, and is benefit for the large scale production of the crystal form I of vecuronium bromide.
Description
Technical field
The present invention relates to the new crystal of vecuronium bromide, and the preparation method of this crystal formation and purposes.
Background technology
Vecuronium bromide (structure as shown in Equation 1) goes on the market in Holland early than nineteen eighty-two, mainly as the general anesthesia adjuvant, is widely used in clinical.It belong to single cropping ammonium steroid in, fugitive non-depolarizing muscular relaxant, can and vagusstoff competition at the nicotinic receptor of striomotor soleplate and the signal conduction between block nerves tip and voluntary muscle, of flaccid muscles while being usually used in general anesthesia in endotracheal intubation and operation.Vecuronium bromide can not discharge histamine after entering human body, and can effectively reduce vomiting possible in the intubate process, mistake is inhaled even the untoward reactions such as anoxic.Than existing muscle relaxants, its drug action is fast, recover rapidly, medication, without accumulating, is the unique a kind of medicine that cardiovascular systems is had no adverse reaction studies confirm that at present repeatedly.
Formula 1
The current vecuronium bromide injection liquid used clinically is mainly freeze-dried powder, and administering mode is two kinds of intravenous injection and intravenous drips.From chemical structure, vecuronium bromide is the basic cpd with two amino, solvability is poor, in conventional formulation, need to add the strongly-acid material to increase the solvability of vecuronium bromide, but this can cause the medicine after dissolving to be acid (PH is about 4.3), thereby produce the ill effect (patent No. CN101843593A) that stimulates blood vessel, causes injection pain.In addition, the existing prepared vecuronium bromide injection of technique, exist water absorbability strong, poor stability, and long-term storage can produce the shortcomings such as a large amount of impurity, and this not only can cause drug quality to descend, and also may bring hiding toxic side effect for clinical use.
Research for the vecuronium bromide preparation at present mainly concentrates on its solvability of increase, stability, reduces these aspects of water absorbability, for example patent publication No. CN101843593A and patent publication No. CN102319215A.Wherein, the former is freeze-dried powder, has that fabrication cycle is long, expense is higher, is unfavorable for saving the shortcoming such as product cost; The auxiliary material amino acid simultaneously added in preparation is unstable, can accelerate the unstable of medicine, and increase preparation cost (seeing CN102319215A).And the latter is in the preparation process of lipidosome injection, the additives such as a large amount of cholesterol, phosphatidylethanolamine, soybean phospholipid, tween 80, PVP have been used, this affected to a certain extent vecuronium bromide curative effect, increased unnecessary clinical risk and hidden danger, and the ratio of each component of adding in preparation process must be carried out strict control, otherwise can greatly reduce quality and the curative effect of injection.Therefore, urgently a kind of raising vecuronium bromide solvability, stability, reduce hygroscopic novel method at present.
We know, for medicine, different crystal formations can have different physical propertiess, as: fusing point, stability, apparent solubility, dissolution rate etc., and these character can directly have influence on stability, solubleness, water absorbability and the bioavailability of pharmaceutical preparation, even final clinical efficacy.Yet there are no the relevant report to the crystal formation of vecuronium bromide.
Summary of the invention
The object of the invention is to, provide solvability and stability all relatively good, can significantly reduce its hygroscopic vecuronium bromide new crystal simultaneously, and related manufacturing processes.
Content of the present invention discloses the crystalline form I of vecuronium bromide, and in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 5.4 ± 0.2,8.8 ± 0.2,12.4 ± 0.2,13.7 ± 0.2,17.6 ± 0.2,19.7 ± 0.2 degree places.
Wherein, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 7.1 ± 0.2,9.4 ± 0.2,16.1 ± 0.2,22.1 ± 0.2,25.1 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 18.8 ± 0.2,20.5 ± 0.2,21.0 ± 0.2,23.2 ± 0.2,26.6 ± 0.2,28.3 ± 0.2 degree places.
Further, in this crystal form X ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
Further preferably, this crystal form X ray powder diffraction is shown in Fig. 1 or Fig. 5.
Further, the means of differential scanning calorimetry endothermic peak of described vecuronium bromide crystalline form I is at 230 ℃-260 ℃.
Further, the fusing point of described vecuronium bromide crystalline form I is at 250.0 ℃-251.0 ℃.
Further, described vecuronium bromide crystalline form I is at 2925 ± 3cm
-1, 2853 ± 3cm
-1, 1743 ± 3cm
-1, 1455 ± 3cm
-1, 1375 ± 3cm
-1, 1228 ± 3cm
-1, 1034 ± 3cm
-1, 1022 ± 3cm
-1there is infrared absorption at place.
The present invention also provides the preparation method of above-mentioned crystalline form I, and it comprises following operation steps:
A) under room temperature or heated condition, vecuronium bromide is dissolved in the haloalkane of C1-2, after charcoal absorption, filters, obtain vecuronium bromide solution;
B) get vecuronium bromide solution, at-25 ℃ to crystallization under room temperature; Perhaps
C) get vecuronium bromide solution, add the ether solvent of C1-6, at-25 ℃ to crystallization under room temperature;
D) separate and obtain crystal, drying, obtain the vecuronium bromide crystalline form I.
Further, in step a), the haloalkane that described haloalkane is C1; In step c), the ether solvent that described ether solvent is C1-4.
Further, in step a), the haloalkane of described C1 is methylene dichloride or chloroform; In step c), the ether solvent of C1-4 is ether, dipropyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane.
Wherein, at step b) and step c) Crystallization Process in, comprise two kinds of modes of standing crystallization or stirring and crystallizing.
Further preferably, in step a), the temperature under heated condition is lower than the boiling point of haloalkane, the 1wt.%-5wt.% that the add-on of gac is vecuronium bromide weight; In step c), the volume ratio of ether solvent and the described haloalkane of step a) is (10:1) ~ (1:6); Wherein, the 2-20 that step a) ~ c), the cumulative volume of solvent load is the vecuronium bromide quality doubly.
Further, step b) or c) in, recrystallization temperature is-25 ℃ ~-20 ℃.
The present invention also provides the purposes of vecuronium bromide crystalline form I in preparing non-depolarizing muscular relaxant.
The present invention also provides a kind of non-depolarizing muscular relaxant composition, and it is that crystalline form I by above-mentioned vecuronium bromide is activeconstituents, adds the preparation that auxiliary material pharmaceutically commonly used is prepared into.
Further, described preparation is injection liquid, and it is to using the vecuronium bromide crystalline form I as activeconstituents, adds that pharmaceutically acceptable auxiliary material and/or vehicle and/or complementary composition be prepared from.
Wherein, described injection conventional excipients or carrier solvent include but are not limited to: sterilized water for injection, glucose injection, sodium chloride injection, Lactated Ringer'S Solution, Dextrose and Sodium Chloride Inj. etc.
Wherein, pharmaceutically acceptable auxiliary material of the present invention is the common agents for the preparation of above-mentioned preparation well known in the art, includes but are not limited to: antioxidant, such as vitamin-E, S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Isotonic regulator, such as glycerine, hydrochloric acid, Citric Acid etc.; Fungistat, such as 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol etc.; Emulsifying agent, such as Yelkin TTS, soybean phospholipid etc.; Solubilizing agent, such as tween 80 etc.
Vecuronium bromide crystalline form I of the present invention, by the change of crystalline structure, improved the solvability of vecuronium bromide, contributes to alleviate or eliminate while injecting the ill effect that stimulates blood vessel, causes pain; Reduce the water absorbability of vecuronium bromide, and significantly strengthened its stability, be conducive to the long-term storage of vecuronium bromide raw material, ensured its security.The preparation technology of vecuronium bromide crystalline form I of the present invention is simple, easy to operate, yield is high, is conducive to the scale operation of vecuronium bromide crystalline form I.
The accompanying drawing explanation
The X-ray powder diffraction (methylene dichloride/ether, standing crystallization) of Fig. 1 embodiment 1 numbering 1 vecuronium bromide crystalline form I made;
The DSC collection of illustrative plates of Fig. 2 embodiment 1 numbering 1 vecuronium bromide crystalline form I made;
The TGA collection of illustrative plates of Fig. 3 embodiment 1 numbering 1 vecuronium bromide crystalline form I made;
The infared spectrum of Fig. 4 embodiment 1 numbering 1 vecuronium bromide crystalline form I made;
The X-ray powder diffraction (methylene dichloride/tetrahydrofuran (THF), stirring and crystallizing) of Fig. 5 embodiment 1 numbering 6 vecuronium bromide crystalline form Is that make;
Fig. 6, according to the method for test example 3, records the high-efficient liquid phase chromatogram of blank sample;
Fig. 7 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide crystalline form I recorded in 0 day;
Fig. 8 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products recorded in 0 day;
Fig. 9 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in illumination after 5 days, the high-efficient liquid phase chromatogram recorded;
Figure 10 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in illumination in 5 days;
Figure 11 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in illumination after 10 days, the high-efficient liquid phase chromatogram recorded;
Figure 12 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in illumination in 10 days;
Figure 13 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in the hot accelerated test of height after 5 days, the high-efficient liquid phase chromatogram recorded;
Figure 14 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in the hot accelerated test of height in 5 days;
Figure 15 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in the hot accelerated test of height after 10 days, the high-efficient liquid phase chromatogram recorded;
Figure 16 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in the hot accelerated test of height in 10 days;
Figure 17 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in the high humidity accelerated test after 5 days, the high-efficient liquid phase chromatogram recorded;
Figure 18 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in the high humidity accelerated test in 5 days;
Figure 19 is according to the method for test example 3, and the vecuronium bromide crystalline form I is in the high humidity accelerated test after 10 days, the high-efficient liquid phase chromatogram recorded;
Figure 20 is according to the method for test example 3, the high-efficient liquid phase chromatogram that the vecuronium bromide currently available products records in the high humidity accelerated test in 10 days.
Embodiment
The preparation of embodiment 1 vecuronium bromide crystalline form I
Vecuronium bromide is placed in to haloalkane solution, and suitably heating, stirring and dissolving, then add a certain amount of gac, filters, and adds a certain amount of ether solvent (add-on of ether solvent and the ratio of haloalkane are in Table 1), and mother liquor is standing/the stirring crystallize out; Collect crystal, drying under reduced pressure, make vecuronium bromide I N-type waferN, and yield is 98%.
In the present invention, the 1wt.%-5wt.% that preferably add-on of gac is vecuronium bromide weight.
The solvent burden ratio of table 1 vecuronium bromide crystalline form I and relevant preparation condition
The detection method of crystal of the present invention comprises:
1, X powder diffraction test
1) sample preparation: directly take sample and make the X diffraction experiment.
2) test apparatus: X ' Pert Pro MPD Philips X-ray powder diffraction instrument
(penetrating source CuK α, graphite monochromator, useful range: 5-50 ° of 2 θ).
3) test conditions: CuK α radiation, graphite monochromator, pipe is pressed 40KV, pipe stream 35mA, 2 θ sweep limit 5-50 °, 9 °/minutes of sweep velocitys, 0.03 ° of step-length.The slit condition: the emission slit is 0.5 °, and accepting slit is 1mm.
2, dsc (DSC) test
Use DSC Q100 analyser, initial temperature is set to 40 ℃, and final temperature is set to 280 ℃, and temperature rise rate is set to 10 ℃/minute (10K/min).
3, infrared measurement test
The use instrument is ThermoFisher Nicolet 6700 Fourier transformation infrared spectrometers, and uses paraffin oil to stick with paste the legal system sheet and detect.
Detect according to the method described above numbering 1 crystal made (the fusing point related data is referring to table 2) in embodiment 1, measure through powder X-ray diffraction, DSC, IR, wherein, DSC is shown in Fig. 2, and IR is shown in Fig. 4, and the X diffracting spectrum is shown in Fig. 1.From each X diffracting spectrum, 2 θ angle of diffraction of this crystalline form I have characteristic peak (the diffraction related data is referring to table 3) at 5.4 ± 0.2,8.8 ± 0.2,12.4 ± 0.2,13.7 ± 0.2,17.6 ± 0.2,19.7 ± 0.2 degree places.
The fusing point data of table 2 vecuronium bromide I N-type waferN
The X-ray powder diffraction data of table 3 vecuronium bromide I N-type waferN
Finding in screening experiment to recrystallization temperature in early stage, when recrystallization temperature is room temperature and-25 ~-20 ℃, all can obtain crystalline form I; But under room temperature, crystal yield is lower, and crystal yield is high-25 ~-20 ℃ the time, and therefore, the present invention preferably adopts-25 ~-20 ℃ to the recrystallization temperature of crystalline form I.
In this experiment, also to numbering 6 crystal that make, carried out the detection of X-powdery diffractometry, result is referring to Fig. 5.
In the present invention, the preparation method of vecuronium bromide used is as follows:
Prepare vecuronium bromide with reference to existing document (CN 101684139A embodiment 8): by 2 β-16 β-bis-(piperidino)-3 α, 17 β-diacetoxy-5 α-etioallocholane 4.5g, ether 35mL are placed in reaction flask and dissolve, ice bath to 0 ℃ left and right, drip the mixing solutions of monobromethane 10mL and ether 10mL, control temperature of reaction during dropping below 10 ℃, about 1h dropwises, and stirring reaction 10h is evaporated to dry after completion of the reaction.
Below prove beneficial effect of the present invention by concrete test example.
The solvability comparative studies of test example 1 vecuronium bromide crystalline form I of the present invention and currently available products
Take trial-product 2g, be placed in the 20ml water of 25 ± 2 ℃, in 10 seconds of powerful jolting every 1 minute, observe the dissolving situation in 3 minutes.As without visual visible particles of solute, be considered as dissolving fully; If visual visible particles of solute is arranged, add 5 times of water gagings, repeat aforementioned operation, until dissolve fully.Record total water amount and time.The results are shown in Table 4.
Wherein, the vecuronium bromide crystalline form I prepares (embodiment 1 numbering 1) by the embodiment of the present invention 1, and the vecuronium bromide currently available products prepares with reference to the existing disclosed method of document (CN 101684139A embodiment 8).
The solvability comparative studies of table 4 crystalline form I and currently available products
As shown in Table 4, vecuronium bromide crystalline form I total water amount of the present invention and dissolution time have obvious shortening compared to currently available products, show that vecuronium bromide crystalline form I of the present invention has obviously improved the water-soluble of vecuronium bromide, its water-soluble currently available products that obviously is better than.
Test example 2 vecuronium bromide crystal formation of the present invention I and the comparative studies of currently available products water absorbability
Get product 1g, drawn moist test (2010 editions second appendix XIX J medicine of Pharmacopoeia of People's Republic of China draws moist test direction principle).
About drawing the defining standard of moist weightening finish:
Deliquescence: absorb enough water and divide formation liquid
Have draw moist: drawing wet weightening finish and being not less than 15%
Have draw moist: drawing wet weightening finish and being less than 15% but be not less than 2%
Slightly draw moist: drawing wet weightening finish and being less than 2% but be not less than 0.2%
Nothing or almost moist without drawing: drawing wet weightening finish and being less than 0.2%
The vecuronium bromide crystalline form I is prepared by the embodiment of the present invention 1, and the vecuronium bromide currently available products prepares with reference to the existing disclosed method of document (CN 101684139A embodiment 8).
Table 5 crystalline form I and currently available products draw moist comparative studies
From table 5, the moisture absorption of vecuronium bromide crystalline form I of the present invention weightening finish is starkly lower than existing vecuronium bromide product, shows that vecuronium bromide crystalline form I of the present invention can significantly reduce the water absorbability of vecuronium bromide, has guaranteed the stability of vecuronium bromide quality.
The study on the stability of test example 3 vecuronium bromide crystalline form I of the present invention and currently available products
The study on the stability condition comprises:
1. thermal destruction: get the about 200mg of trial-product, be placed in 60 ℃ of loft drier and place;
2. photodegradation: get the about 200mg of trial-product, the environment that to be placed in illumination be 4500 ± 500lx is placed;
3. high humidity degraded: get trial-product 200mg, be placed in and be placed with KNO
3in the moisture eliminator of saturated solution, room temperature is placed.Study on the stability the results are shown in Table 7.
The sample detection condition:
Adopt high performance liquid chromatography to be measured
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent, and ammonium chloride-methyl alcohol (20:80) is moving phase, and the detection wavelength is 210nm.
Using vecuronium bromide USP standard substance (purchase obtains) as external standard, calculate each absorption peak area percentage.
Data parsing:
In Fig. 7-20, the chromatographic peak of retention time about 9 minutes is the vecuronium bromide main peak, retention time is respectively the known impurities peak about 4 minutes and 7 minutes, the chromatographic peak that does not indicate retention time in all the other figure is solvent peak and the original chromatographic peak in blank sample, when impurity calculates, should deduct and disregard.
Wherein, the vecuronium bromide crystalline form I is prepared by the embodiment of the present invention 1, and the vecuronium bromide currently available products prepares with reference to the existing disclosed method of document (CN 101684139A embodiment 8).
Foreign matter content in the study on the stability of table 6 crystalline form I and currently available products
From table 6, in exposure experiments to light, strong illumination accelerates 5 days and 10 days, and vecuronium bromide currently available products purity is only 97.875% and 96.994%, is starkly lower than vecuronium bromide crystalline form I of the present invention, and its foreign matter content is 3.7 ~ 4.2 times of vecuronium bromide crystalline form I; In high thermal test, high heat is accelerated 5 days and 10 days, and vecuronium bromide currently available products purity is only 98.078% and 97.167%, is starkly lower than the inventive method vecuronium bromide crystalline form I, and its foreign matter content is 3.6 ~ 4.2 times of vecuronium bromide crystalline form I; In high wet test, high humidity accelerates 5 days and 10 days, and vecuronium bromide currently available products purity is only 97.447% and 96.462%, is starkly lower than vecuronium bromide crystalline form I of the present invention, and its foreign matter content is 3.6 ~ 4.1 times of vecuronium bromide crystalline form I.
Above-mentioned test shows, the vecuronium bromide currently available products is to light, heat, wet less stable, yet, by after its preparation cost invention vecuronium bromide crystalline form I, effectively improved vecuronium bromide to light, heat, wet stability, illustrated that the stability of vecuronium bromide crystalline form I significantly is better than currently available products.
In sum, vecuronium bromide crystalline form I of the present invention, by the change of crystalline structure, significantly improved the solvability of vecuronium bromide, contributes to alleviate or eliminate while injecting the ill effect that stimulates blood vessel, causes pain; Reduce the water absorbability of vecuronium bromide, significantly strengthened its stability, be conducive to the long-term storage of vecuronium bromide raw material, ensured its security.Preparation method, the technique of vecuronium bromide crystalline form I of the present invention is simple, easy to operate, yield is high, is conducive to the scale operation of vecuronium bromide crystalline form I.
Claims (15)
1. the crystalline form I of vecuronium bromide, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 5.4 ± 0.2,8.8 ± 0.2,12.4 ± 0.2,13.7 ± 0.2,17.6 ± 0.2,19.7 ± 0.2 degree places.
2. crystalline form I according to claim 1, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 7.1 ± 0.2,9.4 ± 0.2,16.1 ± 0.2,22.1 ± 0.2,25.1 ± 0.2 degree places.
3. crystalline form I according to claim 2, it is characterized in that: in this crystal form X ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 18.8 ± 0.2,20.5 ± 0.2,21.0 ± 0.2,23.2 ± 0.2,26.6 ± 0.2,28.3 ± 0.2 degree places.
4. crystalline form I according to claim 3, it is characterized in that: in this crystal form X ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
5. crystalline form I according to claim 4, it is characterized in that: this crystal form X ray powder diffraction is shown in Fig. 1 or Fig. 5.
6. according to the described crystalline form I of claim 1-5 any one, it is characterized in that: the means of differential scanning calorimetry endothermic peak of described vecuronium bromide crystalline form I is at 230 ℃-260 ℃.
7. according to the described crystalline form I of claim 1-5 any one, it is characterized in that: the fusing point of described vecuronium bromide crystalline form I is at 250.0 ℃-251.0 ℃.
8. according to the described crystalline form I of claim 1-5 any one, it is characterized in that: described vecuronium bromide crystalline form I is at 2925 ± 3cm
-1, 2853 ± 3cm
-1, 1743 ± 3cm
-1, 1455 ± 3cm
-1, 1375 ± 3cm
-1, 1228 ± 3cm
-1, 1034 ± 3cm
-1, 1022 ± 3cm
-1there is infrared absorption at place.
9. the preparation method of the described crystalline form I of claim 1-8 any one, it is characterized in that: it comprises following operation steps:
A) under room temperature or heated condition, vecuronium bromide is dissolved in the haloalkane of C1-2, after charcoal absorption, filters, obtain vecuronium bromide solution;
B) get vecuronium bromide solution, after naturally being down to room temperature, then be placed in-25 ℃ to crystallization under room temperature; Perhaps
C) get vecuronium bromide solution, after naturally being down to room temperature, then add the ether solvent of C1-6, at-25 ℃ to crystallization under room temperature;
D) separate and obtain crystal, drying, obtain the vecuronium bromide crystalline form I.
10. preparation method according to claim 9 is characterized in that: in step a), and the haloalkane that described haloalkane is C1; In step c), the ether solvent that described ether solvent is C1-4.
11. preparation method according to claim 10 is characterized in that: in step a), the haloalkane of described C1 is methylene dichloride or chloroform; In step c), the ether solvent of C1-4 is ether, dipropyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane.
12. preparation method according to claim 9 is characterized in that: in step a), the temperature under heated condition is lower than the boiling point of haloalkane; The 1wt.%-5wt.% that the add-on of gac is vecuronium bromide weight;
In step c), the volume ratio of ether solvent and the described haloalkane of step a) is (10:1) ~ (1:6);
Wherein, the 2-20 that step a) ~ c), the cumulative volume of solvent load is the vecuronium bromide quality doubly.
13. preparation method according to claim 9 is characterized in that: step b) or c) in, recrystallization temperature is-25 ℃ ~-20 ℃.
14. the purposes of the described vecuronium bromide crystalline form I of claim 1-8 any one in preparing non-depolarizing muscular relaxant.
15. a non-depolarizing muscular relaxant composition is characterized in that: it is that crystalline form I by the described vecuronium bromide of claim 1-8 any one is activeconstituents, adds the preparation that auxiliary material pharmaceutically commonly used is prepared into.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101684139A (en) * | 2008-09-27 | 2010-03-31 | 徐州师范大学 | Synthesis process of vecuronium bromide |
| CN102603850A (en) * | 2011-09-20 | 2012-07-25 | 海南灵康制药有限公司 | Vecuronium bromide compound and production method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101684139A (en) * | 2008-09-27 | 2010-03-31 | 徐州师范大学 | Synthesis process of vecuronium bromide |
| CN102603850A (en) * | 2011-09-20 | 2012-07-25 | 海南灵康制药有限公司 | Vecuronium bromide compound and production method thereof |
Non-Patent Citations (1)
| Title |
|---|
| VAN DER SLUIS P. 等，: "Crystallization of low-molecular-weight organic compounds for x-ray crystallography", 《JOURNAL OF APPLIED CRYSTALLOGRAPH》, vol. 22, no. 4, 31 December 1989 (1989-12-31), pages 340 - 344 * |
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