CN101397329B - Method for preparing rocuronium crystalline hydrate - Google Patents
Method for preparing rocuronium crystalline hydrate Download PDFInfo
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- CN101397329B CN101397329B CN2007100927474A CN200710092747A CN101397329B CN 101397329 B CN101397329 B CN 101397329B CN 2007100927474 A CN2007100927474 A CN 2007100927474A CN 200710092747 A CN200710092747 A CN 200710092747A CN 101397329 B CN101397329 B CN 101397329B
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- crystalline hydrate
- rocuronium
- zemuron
- rocuronium bromide
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Abstract
The invention relates to a preparation method of bulk drugs, in particular to a preparation method of rocuronium bromide crystalline hydrate, which comprises the following steps of: preparing the rocuronium bromide aqueous solution with 2-15 percent of weight volume percent concentration, freezing the aqueous solution to ice under -50-30 DEG C, decompressing and heating up to 30-50 DEG C under vacuum state, keeping 10-20 hours of temperature-rise period and preserving heat for 10-30 hours in vacuum at the temperature. The rocuronium bromide crystalline hydrate prepared by the method enhances the stability of the rocuronium bromide bulk drugs, improves the particle exterior of the rocuronium bromide and effectively reduces the excessive organic residue of the rocuronium bromide bulk drugs.
Description
Technical field
The present invention relates to the preparation method's of bulk drug, particularly rocuronium crystalline hydrate preparation method.
Background technology
Zemuron (Rocuronium Bromide) is to be researched and developed by Organon company, and in June, 1994 and July first in a kind of novel non depolarization sterols muscle relaxant of the U.S. and Britain's listing, its onset is rapid, the intubate condition similar to succinylcholine can be provided, its validity obtains high evaluation, makes major contribution clinically.The chemical structural formula of Zemuron is:
The preparation method and use of Zemuron is disclosed in the European patent EP 0287150; WO0044334 discloses the compound injection of Zemuron and other traditional muscle relaxant compositions; US2006058275 and US2006058276 patent relate to the method for the Zemuron of a kind of pure pressed powder of preparation: its intermediate and excessive bromopropylene are reacted, reaction mixture is poured in the anti-solvent of stirring (crystallization) then, precipitate and separate, the solid of dry wet, dissolve with buffered soln, remove the evaporable solvent, collect drying products.At present, from disclosed patent documentation and non-patent literature, all find no the report that closes the rocuronium crystalline hydrate preparation.
Because Zemuron is the moisture absorption very easily, very unstable, require in the pharmacopeia under the low temperature seal condition, to preserve, this makes that existing Zemuron product is unfavorable for preserving, this will increase the storage cost of manufacturing enterprise and user's medicine undoubtedly, and the storage of medicine brings bigger trouble also for manufacturing enterprise and user.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of rocuronium crystalline hydrate to prepare stable rocuronium crystalline hydrate, increases the stability of Zemuron bulk drug.
The preparation method of rocuronium crystalline hydrate of the present invention is:
Preparation percent weight in volume concentration is 2～15% the Zemuron aqueous solution, with this aqueous solution after glaciation under-50 ℃～-30 ℃ the temperature, decompression is warming up to 30 ℃～50 ℃ under vacuum state, temperature-rise period continues 10～20 hours, and under this temperature vacuum heat-preserving 10～30 hours and make rocuronium crystalline hydrate.
The chemical structural formula of the rocuronium crystalline hydrate that makes according to this method is:
N is 1.5 in the formula.
Because Zemuron exists with the form of crystalline hydrate, so can make its water absorbability be improved significantly, thereby increased the stability of Zemuron bulk drug, and adopt lyophilize that Zemuron is handled, can effectively reduce the excessive organic residual of Zemuron bulk drug, and the form with crystalline hydrate exists, and has also effectively improved the particle appearance of Zemuron.
Because the crystalline hydrate of the existing medicine Zemuron of this Department of Pharmacy, except the stability that increases the Zemuron bulk drug, original property of medicine of Zemuron does not change, so the suitable illness of Zemuron, this crystalline hydrate all can be suitable for, and better effects if.The form of administration of rocuronium crystalline hydrate can be formulations such as injection and powder injection.
Description of drawings
Fig. 1 is the thermogram spectrum of rocuronium crystalline hydrate, and arrow A is represented the heat release direction among the figure, analyzes the crystallization water number according to illustrated data computation
Fig. 2 is the IR collection of illustrative plates of rocuronium crystalline hydrate, is 3435.14cm according to its charateristic avsorption band of diagram
-1, 2930.05cm
-1, 2855.15cm
-1, 1748.10cm
-1, 1640.76cm
-1, 1452.65cm
-1, 1376.42cm
-1, 1224.77cm
-1, 1118.84cm
-1, 1024.88cm
-1
Fig. 3 is the X-ray powder diffraction of rocuronium crystalline hydrate, and as can be seen from the figure this crystalline hydrate is unformed.
Fig. 4 is the mass spectrum of rocuronium crystalline hydrate, illustrates the molecular ion peak m/z610 of Zemuron.
Embodiment
Embodiment one:
Take by weighing Zemuron 3.0g in the single port bottle of 50mL, add 40mL distilled water, the vibration dissolving is poured in the culture dish, then culture dish is put in the Freeze Drying Equipment, the freeze-drying built-in temperature is reduced to-40 ℃, make the freezing solution Cheng Bing in the culture dish, vacuumize, when decompression is warming up to 40 ℃ in 15 hours, insulation vacuum-drying 20 hours gets rocuronium crystalline hydrate (containing 1.5 crystal water) 2.8g.
Ultimate analysis: C32H53BrN2O4.1.5H2O theoretical value C60.28%, H8.79%, Br12.72%, N4.40%, O13.81%; Measured value C60.14%, H8.89%, Br12.64%, N4.37%, O13.96%.The Determination of Residual Organic Solvents of Zemuron is 10.36% before the freeze-drying, and the Determination of Residual Organic Solvents after the freeze-drying in the rocuronium crystalline hydrate is 0.05%.
Embodiment two:
Take by weighing Zemuron 1.5g in the single port bottle of 50mL, add 45mL distilled water, the vibration dissolving is poured in the culture dish, then culture dish is put in the Freeze Drying Equipment, the freeze-drying built-in temperature is reduced to-50 ℃, make the freezing solution Cheng Bing in the culture dish, vacuumize, when decompression is warming up to 50 ℃ in 20 hours, insulation vacuum-drying 30 hours gets rocuronium crystalline hydrate (containing 1.5 crystal water) 1.4g.
Ultimate analysis: C32H53BrN2O4.1.5H2O theoretical value C60.28%, H8.79%, Br12.72%, N4.40%, O13.81%; Measured value C60.23%, H8.81%, Br12.69%, N4.39%, O13.88%.The Determination of Residual Organic Solvents of Zemuron is 10.36% before the freeze-drying, and the Determination of Residual Organic Solvents after the freeze-drying in the rocuronium crystalline hydrate is 0.07%.
Embodiment three:
Take by weighing Zemuron 1.5g in the single port bottle of 50mL, add 10mL distilled water, the vibration dissolving is poured in the culture dish, then culture dish is put in the Freeze Drying Equipment, the freeze-drying built-in temperature is reduced to-30 ℃, make the freezing solution Cheng Bing in the culture dish, vacuumize, when decompression is warming up to 30 ℃ in 10 hours, insulation vacuum-drying 10 hours gets rocuronium crystalline hydrate (containing 1.5 crystal water) 1.3g.
Ultimate analysis: C32H53BrN2O4.1.5H2O theoretical value C60.28%, H8.79%, Br12.72%, N4.40%, O13.81%; Measured value C60.25%, H8.80%, Br12.68%, N4.37%, O13.90%.The Determination of Residual Organic Solvents of Zemuron is 10.36% before the freeze-drying, and the Determination of Residual Organic Solvents after the freeze-drying in the rocuronium crystalline hydrate is 0.04%.
Claims (1)
1. the preparation method of rocuronium crystalline hydrate, it is characterized in that: preparation percent weight in volume concentration is 2～15% the Zemuron aqueous solution, with this aqueous solution after glaciation under-50 ℃～-30 ℃ the temperature, decompression is warming up to 30 ℃～50 ℃ under vacuum state, temperature-rise period continues 10～20 hours, and vacuum heat-preserving formed in 10～30 hours under this temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100927474A CN101397329B (en) | 2007-09-25 | 2007-09-25 | Method for preparing rocuronium crystalline hydrate |
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| CN2007100927474A CN101397329B (en) | 2007-09-25 | 2007-09-25 | Method for preparing rocuronium crystalline hydrate |
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| CN101397329A CN101397329A (en) | 2009-04-01 |
| CN101397329B true CN101397329B (en) | 2011-04-27 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012145888A1 (en) * | 2011-04-25 | 2012-11-01 | 浙江华海药业股份有限公司 | Method for purifying rocuronium bromide |
| CN110734468B (en) | 2018-07-20 | 2021-04-16 | 济南高德医药科技有限公司 | Refining method of rocuronium bromide crude product |
| WO2020088479A1 (en) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | Method for using aqueous solution to prepare single crystal or amorphous substance |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864667A (en) * | 2006-06-02 | 2006-11-22 | 重庆医药工业研究院有限责任公司 | A stable lyophilized preparation of rocuronium bromide and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1864667A (en) * | 2006-06-02 | 2006-11-22 | 重庆医药工业研究院有限责任公司 | A stable lyophilized preparation of rocuronium bromide and preparation method thereof |
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Assignee: Chongqing Dinglian Pharmaceutical Co., Ltd. Assignor: Chongqing Renben Institute of Materia Medica Contract record no.: 2011500000008 Denomination of invention: Method for preparing rocuronium crystalline hydrate License type: Exclusive License Open date: 20090401 Record date: 20110323 |
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Granted publication date: 20110427 Termination date: 20140925 |
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