CN112538124B - Shugansu sodium crystal form - Google Patents
Shugansu sodium crystal form Download PDFInfo
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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Abstract
The invention provides a sodium sugammadex crystal form, and relates to the technical field of crystal form drug molecules. The crystal form of the sodium sugammadex adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta is 5.74+/-0.2 degrees, 7.51+/-0.2 degrees, 10.36+/-0.2 degrees, 12.67+/-0.2 degrees, 16.16+/-0.2 degrees, 17.20+/-0.2 degrees, 17.92+/-0.2 degrees, 19.43+/-0.2 degrees, 20.45+/-0.2 degrees, 21.83+/-0.2 degrees and 22.63+/-0.2 degrees and has characteristic peaks; related methods of preparation and use are also provided. The crystal form of the sodium suger has good stability, the clarity and the color of the solution meet the standard of raw material medicines of injection, and the safety and the stability of the sodium suger injection are improved.
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to a sodium-glucose crystal form.
Background
Sodium supreme glucose (Sugammadex Sodium), chemical name of which is octa-6-perdeoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt, CAS number: 343306-79-6 has the following specific structural formula:
sodium sulmore is a novel muscle relaxant reversing agent, which was developed by the company Organon in the netherlands at the earliest, for reversing the blocking effect of the conventionally used neuromuscular blocking agent rocuronium bromide or vecuronium bromide, and for immediately reversing the effects of rocuronium bromide used by adults and the effects of rocuronium bromide used by children and adolescents (2-17 years). Sodium supreme is the first and only selective relaxant binder (selective relaxant binding agent, SRBA), the first major drug advance in the area of narcotics for 20 years, and has been known as a milestone-like muscle relaxant.
Akzo Nobel has the patent right of 6-mercaptocyclodextrin derivative (bulletin No. CN 1402737A), which is incorporated into Nalingo elegance in 2007 by European currant corporation of the Netherlands, which subsequently developed sugammadex, which was acquired by the moxadong in 2009. The product has been approved in the european union and japan in 2008 and 2010, respectively. FDA approved sodium sulmore glucose injection (trade name: brition) on 12 months 15 days 2015.
In recent years, research shows that the medicine crystal forms are different, and the physicochemical properties (density, hardness, solubility, stability, optical property, electrical property and the like), dissolution rate, biological effect and the like of the medicine crystal forms can be changed, so that the research on the medicine crystal forms has important practical values in the medicine and pharmacy. The crystal form drug molecules comprise polymorphism, hydrate, solvate, salt and the like of the drug molecules, not only can the crystallographic parameters of the crystal form drug molecules be clarified through a drug crystallization way, but also the types and the numbers of solvent molecules (such as crystal water molecules) in the crystal form can be determined, and the crystal form drug molecules have very important roles in understanding and grasping the spatial arrangement and physicochemical properties of the drug molecules.
In the current research report of sodium sulmore crystal form, CN107400182 reports that alcohols such as methanol, ethanol and the like are dropwise added into sodium sulmore aqueous solution to prepare sodium sulmore crystal form A; patent IN201741012475 reports that a sodium Shuganin crystal form is obtained by dropwise adding methanol into a methanol/water mixed solution for crystallization; patent US9879096 discloses the preparation of a sodium sulmore amorphous form; patent CN109053933 reports 5 sodium sulmore forms and one sodium sulmore amorphous form, patent TW201912656 discloses sodium sulmore forms I and II, and reports the formation of sodium sulmore form III by heating form II to cause it to undergo a transcrystalline transformation.
As is well known, sodium sulmore as an effective muscle-relaxing antagonist is used as an injection raw material drug, the injection preparation has strict requirements on various aspects of the raw material drug, and the known sodium sulmore crystal forms cannot well meet the requirements of the drug preparation in terms of clarity, color, solubility, thermal stability, light stability, dissolution rate, bioavailability and the like, so that more crystal forms need to be developed, on one hand, more sodium sulmore crystal forms are provided for drug application, and on the other hand, the drug performance is improved in terms of chemical purity, flowability, solubility, stability (such as storage stability, dehydration stability, polymorphic conversion stability, low hygroscopicity, low residual solvent content), clarity and the like, so that the drug with higher efficiency is developed; on the other hand, the sodium gluconate crystal form which is more suitable for industrial production and has high economic benefit is also developed.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, it is an object of the present invention to provide a crystalline form of sodium sugammadex; another object of the invention is to provide a process for the preparation of the crystalline form of sodium supreme glucose; it is also an object of the present invention to provide the use of a crystalline form of sodium supreme in the preparation of a muscle relaxant drug.
The specific technical scheme of the invention is as follows:
a crystal form of sodium sugammadex is prepared by using Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 7.51+/-0.2 degrees, 10.36+/-0.2 degrees, 16.16+/-0.2 degrees, 17.20+/-0.2 degrees and 17.92+/-0.2 degrees.
Preferably, the crystal form of the sodium sugammadex uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.74+/-0.2 degrees, 7.51+/-0.2 degrees, 10.36+/-0.2 degrees, 12.67+/-0.2 degrees, 16.16+/-0.2 degrees, 16.64+/-0.2 degrees, 17.20+/-0.2 degrees, 17.92+/-0.2 degrees, 19.00+/-0.2 degrees, 19.43+/-0.2 degrees, 20.45+/-0.2 degrees, 21.83+/-0.2 degrees and 22.63+/-0.2 degrees.
Preferably, the crystalline form of sodium supreme glucose is irradiated with Cu-K alpha, the characteristic peaks of which correspond to the X-ray powder diffraction pattern shown in figure 1.
The preparation method of the sodium sugammadex crystal form comprises the following steps:
under the protection of inert gas, adding sodium sulfanilamide into the mixed solution of the organic solvent A and the purified water, controlling the temperature to reflux and reacting, filtering after the reaction is finished, and slowly cooling the filtrate; after cooling, dropwise adding the organic solvent B under heat preservation and stirring, and after dropwise adding, performing heat preservation and stirring for crystallization; and after crystallization, filtering, and drying a filter cake to obtain white crystalline sodium gluconate.
Preferably, the organic solvent A is one or two of methanol, ethanol, isopropanol, tertiary butanol, ethylene glycol and propylene glycol; tertiary butanol is preferred.
Preferably, the volume ratio of the organic solvent A to the purified water is 1:1 to 2.
Preferably, the mass-volume ratio of the sodium metaglucopyranose to the mixed solution is 1:3-5 g/ml.
Preferably, the temperature-controlled reflux reaction time is 1 to 2 hours.
Preferably, the filtrate is slowly cooled to 20-30 ℃.
In a preferred embodiment, the slow cooling mode of the filtrate is programmed cooling, preferably, the cooling rate is 0.5 ℃/min.
Preferably, the organic solvent B is one or two of methanol, ethanol, acetonitrile, acetone, N-dimethylformamide, isopropanol, tertiary butanol, tetrahydrofuran, 1, 4-dioxane, ethylene glycol and propylene glycol; acetonitrile is preferred.
Preferably, the amount of the organic solvent B is an appropriate amount for achieving the maximum precipitation amount of sodium digluconate; wherein the mass volume ratio of the sodium sulmore glucose to the organic solvent B is preferably 1:10-20 g/ml.
Preferably, the crystallization time is 2 to 3 hours.
Preferably, the temperature of the heat-preserving dropwise adding of the organic solvent B and stirring crystallization is 20-30 ℃.
In the present invention, the inert gas is usually nitrogen or argon, and among them, argon is particularly preferable.
The application of the crystalline form of the sodium suger as an active ingredient in preparing a muscle relaxation antagonist drug.
An injectable formulation comprising the crystalline form of sodium supreme glucose according to the invention, mixed with other components.
Preferably, the preparation method of the injection preparation of the invention is as follows: the compounds of the present invention are formulated into injectable formulations by combining them with a pharmaceutically acceptable solid or liquid carrier, and optionally with a pharmaceutically acceptable excipient, using standard and conventional techniques.
Preferably, the preparation can be a ready-to-use liquid injection or a freeze-dried powder injection.
Preferably, other components of the formulation include other active ingredients, osmolality adjusting agents, pH adjusting agents, solubilizing agents, co-solvents, antioxidants, bacteriostats, emulsifiers, complexing agents and the like, which may be used in combination.
More preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, fructose, glycerol, sorbitol, xylitol, magnesium chloride, phosphate, sodium citrate and mannitol; the pH regulator is selected fromOne or more of hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate and arginine; the solubilizer is one or more selected from Tween 80, tween 60, poloxamer 68; the cosolvent is selected from sodium benzoate, sodium salicylate, sodium p-aminobenzoate, uratein, urea, erucamide, glucose, meglumine, malic acid, methionine, glycine, arginine, nicotinamide, sodium bicarbonate, phenylalanine, and vitamin B 6 One or more of the following; the antioxidant is one or more selected from L-cysteine hydrochloride, sodium sulfite, sodium bisulphite, propyl gallate, glutathione, sodium thiosulfate, thiourea, thioglycollic acid, sodium metabisulfite and vitamin B; the bacteriostat is one or more selected from the group consisting of; the emulsifier is one or more selected from lecithin, soybean lecithin, poloxamer 68, cholesterol and glycerol monooleate; the complexing agent is selected from one or more of disodium ethylenediamine tetraacetate and calcium ethylenediamine tetraacetate disodium salt.
The invention has the beneficial effects that:
1. the preparation method of the sodium gluconate crystal form is simple, the production equipment requirement is low, and the purity and the yield of the obtained product are high, so that the sodium gluconate crystal form is suitable for large-scale popularization and application.
2. The sodium gluconate crystal form of the invention has the advantages of basically no increase of test impurities, better stability and ensured drug effect while being beneficial to drug storage.
3. The solution of the crystal form of sodium suger in the invention has qualified clarity and color, and improves the safety and stability of sodium suger injection preparation.
Drawings
Fig. 1: x-ray powder diffraction pattern of sodium sugammadex crystal form.
Fig. 2: a differential scanning calorimetry (DSC/TGA) profile of the sodium digluconate crystalline form.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: sodium sulmore gluconate is commercially available and can also be prepared with reference to the prior art; the materials used in the other experiments were not of the indicated source and specification, either commercially available analytically pure or chemically pure.
The invention adopts HPLC to measure the purity of the sodium sulmore gluconate, and the chromatographic conditions are as follows:
chromatographic column: phenomnex, aqua-C 18( 2.0mm×150mm,3.0μm)；
Mobile phase: mobile phase a:25.0mmol/L phosphate buffer (pH=3.0) (3.45 g of sodium dihydrogen phosphate monohydrate is taken, placed in a 1000ml volumetric flask, 950ml of water is added, the pH is adjusted to 3.00+ -0.03 with 1.5mol/L phosphate solution, and diluted to scale with water, shaken) -acetonitrile (83:20); mobile phase B: acetonitrile;
column temperature: 40 ℃;
detection wavelength: 200nm;
flow rate: 0.27ml/min;
sample injection amount: 2.5 μl;
the elution gradient is shown in Table 1, wherein the retention time of sodium supreme (8-substitute) is between about 20.5min and about 23.0min, the retention time of 7-substitute of the minor active ingredient is about 0.65 times the main peak retention time, and the purity of sodium supreme is calculated as the sum of the product of the 7-substitute and 8-substitute.
TABLE 1 elution gradient table
Example 1
Sodium supreme gluconate (5.05 g) was added to t-butanol/purified water (V) Tert-butanol :V Water and its preparation method =1:1.5, 20 ml), reflux-reacting for 1 hour at controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃, acetonitrile (75 ml) is added dropwise while stirring,after the dripping is finished, preserving heat, stirring and crystallizing for 2 hours; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 97.8% and a purity of 99.89%.
Example 2
Sodium supreme gluconate (5.02 g) was added to methanol/purified water (V) Methanol :V Water and its preparation method =1:1, 25 ml), reflux-reacting for 2 hours at controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding methanol (60 ml) while stirring, and preserving heat, stirring and crystallizing for 2 hours after the dropwise adding is finished; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 95.6% and a purity of 99.78%.
Example 3
Sodium supreme gluconate (5.08 g) was added to ethanol/purified water (V) Ethanol :V Water and its preparation method =1:2, 15 ml), reflux-reacting for 1 hour at controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding methanol (80 ml) while stirring, and preserving heat, stirring and crystallizing for 3 hours after the dropwise adding is finished; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 95.8% and a purity of 99.76%.
Example 4
Sodium supreme gluconate (5.01 g) was added to isopropanol/purified water (V) Isopropyl alcohol :V Water and its preparation method =1:1.6, 22 ml), reflux-reacting for 1 hour at controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃, N-dimethylformamide (85 ml) is added dropwise under stirring, and after the completion of the dropwise addition, the mixture is stirred for crystallization for 3 hours under heat preservation; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 96.2% and a purity of 99.74%.
Example 5
Sodium supreme gluconate (5.03 g) was added to ethylene glycol/purified water (V) Ethylene glycol :V Water and its preparation method =1:1.2, 25 ml)In the mixed solution, reflux reaction is carried out for 2 hours under controlled temperature, the reaction is finished, the mixture is filtered, and the filtrate is cooled to 20-30 ℃ at the speed of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃, acetone (70 ml) is added dropwise under stirring, and after the addition, the mixture is stirred and crystallized for 2 hours under heat preservation; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 96.3% and a purity of 99.72%.
Example 6
Sodium supreme gluconate (5.06 g) was added to propylene glycol/purified water (V) Propylene glycol :V Water and its preparation method =1:1.5, 20 ml), reflux-reacting for 2 hours at a controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding isopropanol (90 ml) while stirring, and preserving heat, stirring and crystallizing for 3 hours after the dropwise adding is finished; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 95.9% and a purity of 99.78%.
Example 7
Sodium supreme gluconate (5.05 g) was added to methanol/purified water (V) Methanol :V Water and its preparation method =1:1, 20 ml), reflux-reacting for 2 hours at controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; controlling the temperature of the reaction liquid to be 20-30 ℃, dropwise adding tetrahydrofuran (100 ml) while stirring, and preserving heat, stirring and crystallizing for 2 hours after the dropwise adding is finished; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 96.3% and a purity of 99.74%.
Example 8
Sodium supreme gluconate (5.02 g) was added to t-butanol/purified water (V) Tert-butanol :V Water and its preparation method =1:1.5, 20 ml), reflux-reacting for 2 hours at a controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃,1, 4-dioxane (80 ml) is added dropwise under stirring, and after the completion of the addition, the mixture is stirred for crystallization for 3 hours under heat preservation; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 96.4% and a purity of 99.76%.
Example 9
Sodium supreme gluconate (5.07 g) was added to ethanol/purified water (V) Ethanol :V Water and its preparation method =1:1.5, 20 ml), reflux-reacting for 2 hours at a controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃, and glycol (65 ml) is added dropwise under stirring, and after the dripping is finished, the mixture is stirred and crystallized for 2 hours under heat preservation; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 95.6% and a purity of 99.73%.
Example 10
Sodium supreme gluconate (5.04 g) was added to isopropanol/purified water (V) Isopropyl alcohol :V Water and its preparation method =1:1.5, 20 ml), reflux-reacting for 2 hours at a controlled temperature, ending the reaction, filtering, and cooling the filtrate to 20-30 ℃ at a rate of 0.5 ℃/min; the temperature of the reaction liquid is controlled to be 20-30 ℃, propylene glycol (70 ml) is added dropwise under stirring, and after the dripping is finished, the mixture is stirred and crystallized for 2 hours under heat preservation; after crystallization, filtering, and drying the filter cake at 40 ℃ under reduced pressure to constant weight to obtain white crystalline sodium sulmore gluconate with a yield of 96.1% and a purity of 99.80%.
Confirmation of Crystal form Structure
The X-ray powder diffraction test instrument and test conditions related in the invention: an X-ray powder diffractometer, PANalytical E; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg. The characteristic peaks in the X-ray powder diffraction diagram (Cu-K alpha) corresponding to the sodium gluconate crystal form are shown in figure 1 and table 2.
TABLE 2 sodium Shuganglucose form PXRD peak
The samples of examples 1-10 all have the same X-ray powder diffraction pattern.
Comparative examples 1 to 11 sodium sulmore gluconate was prepared with reference to the preparation methods of the crystal forms of sodium sulmore gluconate reported heretofore.
Comparative example 1
Sodium sulmore gluconate (46 g) is added into a mixed solution of purified water (69 ml)/methanol (69 ml), activated carbon (11.5 g) is added after stirring and dissolving at 25-35 ℃, stirring is performed for 30min at 25-35 ℃, filtering is performed, filter cake is washed by water (23 ml)/methanol (23 ml), filtrate is controlled at 25-35 ℃, methanol (598 ml) is added and stirred for 2 hours, filtering is performed, filter cake methanol (184 ml) is washed, drying is performed at 55-60 ℃ for 14 hours, and crystalline sodium sulmore gluconate is obtained, yield is 55.3%, and pure 99.62%.
Comparative example 2
Sodium supreme (10.9 g) was added to a mixed solution of purified water (15 ml)/methanol (15 ml), activated carbon (2 g) was added, and the mixture was filtered, and the cake was washed with purified water (5 ml); adding methanol (135 ml) into the filtrate at 50-55deg.C, stirring at 50-55deg.C for 2 hr, precipitating solid, filtering, washing the filter cake with methanol (20 ml), and vacuum drying at 70-75deg.C for 24 hr to obtain amorphous sodium sulfatase with yield of 62.4% and purity of 99.53%.
Comparative example 3
Adding sodium sulmore gluconate (5 g) into purified water (10 ml), stirring for dissolution, heating to 50-60 ℃, slowly dropwise adding methanol (60 ml), precipitating solid after adding, naturally cooling to room temperature, further cooling to 0-5 ℃, preserving heat for 1 hour, filtering, and drying to obtain the sodium sulmore gluconate crystal with the yield of 86.2% and the purity of 99.64%.
Comparative example 4
Adding sodium sugammadex (10 g) into purified water (20 ml), stirring to dissolve, heating to 60deg.C, adding ethanol (120 ml) under stirring, and precipitating a large amount of white solid; naturally cooling to room temperature, further cooling to 0 ℃, preserving heat and stirring for 1 hour, carrying out suction filtration, and drying a filter cake to obtain the crystalline sodium digluconate with the yield of 88.4% and the purity of 99.56%.
Comparative example 5
Sodium sulmore gluconate (10 g) is added into purified water (20 ml), stirred and dissolved, heated to 75 ℃, DMF (60 ml) is added under stirring, and a large amount of white solid is precipitated; naturally cooling to room temperature, suction filtering, and drying a filter cake to obtain the crystalline sodium digluconate with the yield of 88.7% and the purity of 99.62%.
Comparative example 6
Adding sodium sulmore gluconate (10 g) into purified water (20 ml), stirring to dissolve, heating to 50deg.C, adding acetone (160 ml) under stirring, and precipitating a large amount of white solid; naturally cooling to room temperature, further cooling to 0 ℃, preserving heat and stirring for 1 hour, carrying out suction filtration, and drying a filter cake to obtain the crystalline sodium digluconate with the yield of 87.3% and the purity of 99.58%.
Comparative example 7
Adding sodium sulmore gluconate (10 g) into purified water (20 ml), stirring to dissolve, placing the solution into a flat bottom tray, placing into a freeze dryer, pre-freezing to-80 ℃, heating in gradient, and freeze drying for 24 hours to obtain sodium sulmore crystal sulmore gluconate with purity of 99.34%.
Comparative example 8
Sodium sulmore gluconate (10 g) is added into purified water (50 ml), stirred and dissolved, the temperature is raised to 75 ℃ under stirring, the stirring rotation speed is 200r/min, 1, 4-dioxane (300 ml) is added into the solution dropwise, the stirring is cooled to room temperature, a large amount of white solid is separated out, the filtration is carried out, the filter cake is dried to dryness under vacuum, and amorphous sodium sulmore gluconate is obtained, the yield is 90.8%, and the purity is 99.66%.
Comparative example 9
Adding sodium sulmore gluconate (10 g) into purified water (30 ml), and stirring to dissolve to obtain sodium sulmore gluconate aqueous solution; DMF (75 ml) was added to the aqueous sodium sulmore gluconate solution for crystallization, stirred at 25℃for crystallization for 1 hour, filtered, and the filter cake was washed with a water/DMF (20 ml. Times.2) mixed solution to obtain crystalline sodium sulmore gluconate in a yield of 86.7% and a purity of 99.58%.
Comparative example 10
Crystalline sodium sulmore gluconate was prepared by the method of comparative example 9, and methanol (480 ml) was added after adding purified water (3 ml) to the prepared crystalline sodium sulmore gluconate (93 g); heating the reaction solution to 65 ℃ to clarify the reaction solution and slowly cooling; cooling to 42-45deg.C, maintaining the temperature and stirring for 2 hr, crystallizing; the reaction solution is continuously cooled to 25 ℃, stirred and crystallized for 2 hours at the temperature of 25 ℃, filtered, and the filter cake is washed by water/methanol (20 ml multiplied by 2) mixed solution to obtain sodium crystalline sodium gluconate with the yield of 80.2 percent and the purity of 99.62 percent.
Comparative example 11
The sodium crystalline suplucose (5 g) prepared in comparative example 10 was dried by heating to 80-90℃for 12 hours under vacuum (15 mmHg) to obtain sodium crystalline suplucose with a purity of 99.64%.
Thermal stability test
The sodium supreme glucose prepared in example 1 and comparative examples 1 to 11 was dissolved in water, and then stored in the dark at 25℃for 6 months, and the impurity content was measured by sampling for 1 month, 3 months and 6 months, respectively, and the purity measurement of sodium supreme glucose was measured by referring to HPLC. The results are shown in Table 3.
TABLE 3 stability test results in sodium Shuganglucose solution
As shown in table 3, the stability test results of sodium sulmore gluconate solution stored in the dark at 25 ℃ showed that the impurities of amorphous sodium sulmore gluconate of comparative example 2 and comparative example 8 were significantly increased, and the impurities were all over 1% after 3 months of stability examination; other comparative examples show that the impurity is greater than 0.5 after 6 months of investigation; the stability test result of the sodium gluconate crystal form solution shows that the impurity change is not obvious and basically stable; the results of stability tests similar to those of examples 1 to 10 of the present invention were found.
The sodium supreme glucose prepared in example 1 and comparative examples 1 to 11 was subjected to accelerated test in the dark at 40℃ (RH 45%) for 6 months, and samples were taken for 1 month, 3 months and 6 months to measure the impurity content, respectively, and the purity measurement of sodium supreme glucose was measured by referring to HPLC. The results are shown in Table 4.
TABLE 4 results of accelerated test at 40℃in solid state of sodium Shuganglucose
The solid stability test results show that the impurities of the amorphous sodium sulmore gluconate of the comparative example 2 and the comparative example 8 are obviously increased, and the impurities are more than 1% after 3 months of stability inspection; other comparative examples show that the impurity is greater than 0.5 after 6 months of investigation; the results of the solid stability test of the sodium gluconate crystal form show that the impurity changes are not obvious and are basically stable; the results of stability tests similar to those of examples 1 to 10 of the present invention were found.
Light stability test
The sodium supreme prepared in example 1 and comparative examples 1 to 11 was taken and the impurity content was detected by irradiation with strong light (4500 lx.+ -. 500 Lx) for 0, 15 and 30 days, respectively, and the purity of sodium supreme was measured by HPLC. The results are shown in Table 5.
TABLE 5 sodium dextrose photostability test results
The photo stability test result shows that under the condition of strong light irradiation, the impurity change of the crystal form of the sodium gluconate is not obvious, the photo stability is better, and the dosage form prepared by the crystal form of the sodium gluconate is beneficial to medicine storage and ensures the medicine effect; the amorphous sodium sulmore photo test results of comparative example 2 and comparative example 8 show a significant increase in impurities and poor light stability; examples 1 to 10 of the present invention were examined and found to have similar light stability test results.
Clarity and color test
The sodium supreme glucose prepared in example 1 and comparative examples 1 to 11 was subjected to accelerated test in the dark at 40℃for 6 months, and samples were taken at the initial stage, 1 month, 3 months, and 6 months, respectively, to examine the clarity and color of the sample solution. Referring to the registration mark (JX 20140183) of the Shugansu sodium injection, the clarity detection of a sample solution refers to the Chinese pharmacopoeia 2015 edition four general rules 0902; color detection of sample solution, taking ultrapure water as blank solution, and measuring absorbance (should be less than 0.75) at 350nm wavelength according to ultraviolet-visible spectrophotometry (China pharmacopoeia 2015 edition four division general rule 0401). The results are shown in Table 6.
TABLE 6 results of accelerated test at 40℃in sodium Shuganglucose solid state
After the sodium gluconate crystal form is accelerated for 6 months for investigation, the clarity is less than 0.5 turbidity, and the absorbance is less than 0.75 after color detection, so that the standard of the injection raw material medicine is reached. Examples 1 to 10 of the present invention were found to have similar clarity and color test results.
Claims (7)
1. A crystalline form of sodium supreme, characterized in that said crystalline form of sodium supreme has an X-ray powder diffraction pattern as shown in figure 1.
2. A process for preparing the crystalline form of sodium comfort glucose of claim 1, comprising the steps of:
under the protection of inert gas, adding sodium sulfanilamide into the mixed solution of the organic solvent A and the purified water, controlling the temperature to reflux and reacting, filtering after the reaction is finished, and slowly cooling the filtrate; after cooling, dropwise adding the organic solvent B under heat preservation and stirring, and after dropwise adding, performing heat preservation and stirring for crystallization; after crystallization, filtering, and drying a filter cake to obtain white crystalline sodium gluconate; the filtrate is slowly cooled in a program cooling mode, the cooling rate is 0.5 ℃/min, and the filtrate is slowly cooled to 20-30 ℃.
3. The preparation method of the sodium sugammadex crystal form according to claim 2, wherein the organic solvent A is one or two of methanol, ethanol, isopropanol, tert-butanol, ethylene glycol and propylene glycol.
4. The method for preparing a crystalline form of sodium sugammadex according to claim 2, characterized in that the volume ratio of organic solvent a to purified water is 1: 1-2; the mass volume ratio of the sodium suger to the mixed solution is 1:3-5, g/ml.
5. The preparation method of the sodium sugammadex crystal form according to claim 2, wherein the organic solvent B is methanol, ethanol, acetonitrile, acetone,N，N-one or two of dimethylformamide, isopropanol, tert-butanol, tetrahydrofuran, 1, 4-dioxane, ethylene glycol, propylene glycol; the mass volume ratio of the sodium suger to the organic solvent B is 1:10-20, g/ml.
6. The preparation method of the sodium sugammadex crystal form according to claim 2, wherein the temperature of dropwise adding the organic solvent B at the temperature of 20-30 ℃ and stirring crystallization is carried out.
7. Use of the crystalline form of sodium supreme as claimed in claim 1 as active ingredient for the preparation of a muscle relaxant drug.
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