CN116606388A - Alpha crystal form of sodium sugammadex and preparation method thereof - Google Patents
Alpha crystal form of sodium sugammadex and preparation method thereof Download PDFInfo
- Publication number
- CN116606388A CN116606388A CN202310679473.8A CN202310679473A CN116606388A CN 116606388 A CN116606388 A CN 116606388A CN 202310679473 A CN202310679473 A CN 202310679473A CN 116606388 A CN116606388 A CN 116606388A
- Authority
- CN
- China
- Prior art keywords
- alpha
- sodium
- solid
- ray powder
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 79
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 59
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 59
- 239000011734 sodium Substances 0.000 title claims abstract description 59
- 229920002370 Sugammadex Polymers 0.000 title claims abstract description 23
- WHRODDIHRRDWEW-VTHZAVIASA-N sugammadex Chemical compound O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC(O)=O)O)[C@H](CSCCC(O)=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC(O)=O)O1 WHRODDIHRRDWEW-VTHZAVIASA-N 0.000 title claims abstract description 23
- 229960002257 sugammadex Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 26
- 230000005855 radiation Effects 0.000 claims abstract description 12
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 22
- 239000012065 filter cake Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 10
- 239000008103 glucose Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 230000001747 exhibiting effect Effects 0.000 claims description 8
- 238000004537 pulping Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000005286 illumination Methods 0.000 description 13
- 229960003682 rocuronium bromide Drugs 0.000 description 11
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 238000013112 stability test Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 6
- 229940005574 sodium gluconate Drugs 0.000 description 6
- 235000012207 sodium gluconate Nutrition 0.000 description 6
- 239000000176 sodium gluconate Substances 0.000 description 6
- 230000008485 antagonism Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003158 myorelaxant agent Substances 0.000 description 4
- 102000005262 Sulfatase Human genes 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 108060007951 sulfatase Proteins 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 210000000715 neuromuscular junction Anatomy 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 229960004298 vecuronium bromide Drugs 0.000 description 2
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 229940123126 Selective relaxant binding agent Drugs 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- QTSYXIBPHXTELL-HXIISURNSA-N [Na].O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO Chemical compound [Na].O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO QTSYXIBPHXTELL-HXIISURNSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 229960001862 atracurium Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IZTUINVRJSCOIR-UHFFFAOYSA-N benzylisoquinoline Chemical compound N=1C=CC2=CC=CC=C2C=1CC1=CC=CC=C1 IZTUINVRJSCOIR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- 239000002715 neuromuscular depolarizing agent Substances 0.000 description 1
- 239000003156 neuromuscular nondepolarizing agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229940126589 solid medicine Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 1
- 229940032712 succinylcholine Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application discloses an alpha crystal form of sodium sugammadex and a preparation method thereof, wherein Cu-Ka radiation is used for obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta, and characteristic peaks are displayed at the 2 theta positions of 5.966,6.308,7.408,8.384, 11.960, 17.869, 18.925, 21.466, 21.851, 22.320 and 36.414 degrees; characteristic peaks are shown at 2θ of 5.965,6.269,7.405,8.405, 10.183, 11.976, 13.302, 13.975, 14.842, 15.770, 17.889, 18.314, 18.886, 20.284, 21.547, 21.850, 22.403, 23.902, 27.175, 29.962, 33.186 degrees; characteristic peaks are shown at 2θ of 5.925,6.327,7.322,8.382,8.994, 10.068, 10.675, 11.877, 12.428, 13.292, 14.520, 15.618, 17.218, 17.870, 18.807, 19.107, 20.206, 21.808, 22.358, 23.942, 24.223, 25.806, 26.260, 27.111, 33.143 degrees; characteristic peaks are shown at 2θ of 5.966,6.293,7.448,8.422, 10.109, 11.917, 13.306, 16.880, 17.888, 18.887, 20.290, 21.471, 21.812, 21.873, 23.840, 25.929, 33.351, 47.243; characteristic peaks are shown at 2θ of 5.559,5.967,6.348,7.349,8.404, 10.051, 10.761, 11.896, 13.302, 14.754, 15.669, 17.911, 18.805, 19.149, 20.265, 21.768, 22.377, 23.880, 24.040, 24.189, 26.885, 27.187, 29.533, 30.007, 38.456 with an error value of +/-0.2 °.
Description
Technical Field
The application relates to an alpha crystal form of sodium sugammadex and a preparation method thereof.
Background
Chemical name of sodium sugammadex: 6-perdeoxy-6-per (2-carboxyethyl) thio- γ -cyclodextrin sodium salt, english: su gamma dex, trade name: brision, sodium supreme, was first discovered by Organon Biosciences, and 2007 organic was purchased from Schering-Plough. first-note-Sulbaoya and Merck (Merck) were combined in 2009. Sodium gluconate is currently owned and marketed by merck.
The sodium sugammadex is used for reversing the action of the neuromuscular blocking drug rocuronium bromide or vecuronium bromide which is conventionally used, and can immediately reverse the action of the rocuronium bromide which is used by adults and the action of the rocuronium bromide which is conventionally used by children and teenagers (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.
The mechanism of supreme sodium gluconate muscle relaxation antagonism is: sodium sulmore chelate free rocuronium bromide molecules in the plasma, causing the plasma free rocuronium bromide concentration to drop sharply, creating a concentration gradient between the effector compartment (at the neuromuscular junction) and the central compartment (plasma), causing rapid transport of rocuronium bromide molecules in the effector compartment to the central compartment along the concentration difference, which causes rapid drop in the rocuronium bromide concentration in the effector compartment, and rapid release of rocuronium bromide bound to the nicotinic acetylcholine receptor at the neuromuscular junction, thus reversing the muscle relaxant effect of rocuronium bromide. Antagonism of the muscle relaxant by sodium diglucose is highly selective. Because the inner cavity of the drug has complementarity with rocuronium bromide molecules, the selective antagonism steroid muscle relaxant rocuronium bromide has good antagonism on similar drugs of vecuronium bromide, but has no antagonism on benzyl isoquinoline non-depolarizing muscle relaxants (such as atracurium, etc.) and depolarizing muscle relaxants (succinylcholine).
Sodium supreme is prepared as crystals for better clinical use, and chemical properties, stability and the like of solid medicines are known to be significantly changed when the crystal forms of the medicines are different. The difference between the free energy of the polymorphic forms and the difference between the acting forces among the molecules can lead to the difference between the solubility of the medicines, so that the difference between the dissolution rate and the bioavailability of the medicines can be caused, thereby affecting the absorption process of the medicines in vivo and further leading to the difference of the curative effect of the medicines (see paraYino and Yan Gongkuan of the literature, polymorphic forms of the medicines, chinese western medicine impurities, 2000, 15 (3): 197-9). The prior prepared sodium crystalline sodium sulmore has problems in terms of clarity and stability, and in order to solve the problems, the inventors of the present application invented an alpha crystal form of sodium sulmore and a preparation method thereof.
Disclosure of Invention
An alpha-crystalline form of sodium sugammadex characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ using Cu-Ka radiation, exhibiting characteristic peaks at 5.966,6.308,7.408,8.384, 11.960, 17.869, 18.925, 21.466, 21.851, 22.320, 36.414 degrees 2θ with an error value +/-0.2 °.
An alpha-crystalline form of sodium sugammadex characterized by the use of Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 5.965,6.269,7.405,8.405, 10.183, 11.976, 13.302, 13.975, 14.842, 15.770, 17.889, 18.314, 18.886, 20.284, 21.547, 21.850, 22.403, 23.902, 27.175, 29.962, 33.186 degrees of 2θ with an error value +/-0.2 °.
An alpha-crystalline form of sodium sugammadex characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ using Cu-Ka radiation, showing characteristic peaks at 2θ of 5.925,6.327,7.322,8.382,8.994, 10.068, 10.675, 11.877, 12.428, 13.292, 14.520, 15.618, 17.218, 17.870, 18.807, 19.107, 20.206, 21.808, 22.358, 23.942, 24.223, 25.806, 26.260, 27.111, 33.143 with an error value +/-0.2 °.
An alpha-crystalline form of sodium sugammadex characterized by the fact that, using Cu-Ka radiation, an X-ray powder diffraction pattern is obtained expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 2θ of 5.966,6.293,7.448,8.422, 10.109, 11.917, 13.306, 16.880, 17.888, 18.887, 20.290, 21.471, 21.812, 21.873, 23.840, 25.929, 33.351, 47.243 with an error value of +/-0.2 °.
An alpha-crystalline form of sodium sugammadex characterized by the use of Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 2θ of 5.559,5.967,6.348,7.349,8.404, 10.051, 10.761, 11.896, 13.302, 14.754, 15.669, 17.911, 18.805, 19.149, 20.265, 21.768, 22.377, 23.880, 24.040, 24.189, 26.885, 27.187, 29.533, 30.007, 38.456 with an error value of +/-0.2 °.
A process for the preparation of alpha-form of sodium supreme glucose as claimed in any one of the preceding claims, characterized in that,
step one: adding the sodium sugammadex crude product into a solvent, stirring and dispersing, adding purified water for dissolution, stirring and heating the system to 60-100 ℃, cooling to just precipitate solid in the system, keeping the temperature and stirring, continuously cooling to and stirring for crystallization, and filtering to obtain solid;
step two: and leaching the solid filter cake, drying in vacuum to obtain a solid, pulping and filtering the solid, leaching the filter cake, and drying in vacuum to obtain the novel crystal form alpha crystal.
The above-mentioned production method is characterized in that the solvent is an alcoholic solvent, and methanol is more preferable.
The preparation method is characterized in that in the first step, the temperature is raised to 65-80 ℃, the heat preservation and stirring time is 1.5-3 hours, more preferably the temperature is lowered to 30-60 ℃ when the system is just in solid precipitation, still more preferably the temperature is lowered to 40-50 ℃ when the system is just in solid precipitation.
The preparation method is characterized in that the conditions of the second step are as follows: and pulping the solid filter cake with ethanol for 1-2 hours, filtering, leaching the filter cake with ethanol, and drying at the temperature of 80-90 ℃ for 23-25 hours.
A pharmaceutical composition comprising sodium sugammadex in any of the crystalline forms described above and a pharmaceutically acceptable carrier or excipient.
Effects of the application
The alpha crystal form of the sodium sulmore is better in stability at high temperature and illumination than beta crystal form, gamma crystal form and theta crystal form, can be kept clear even under high-temperature illumination, has high purity, and is beneficial to pharmaceutical utilization.
Drawings
FIG. 1 is an alpha 1-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 2 is an alpha 2-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 3 is an alpha 3-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 4 is an alpha 4-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 5 is an alpha 5-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 6 is a beta-X ray powder diffraction pattern of sodium supreme glucose;
FIG. 7 is a gamma-X ray powder diffraction pattern of sodium supreme glucose;
fig. 8 is a theta-X-ray powder diffraction pattern of sodium sugammadex.
Detailed Description
The technical solutions of the embodiments of the present application will be clearly described below with reference to the drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments, which are obtained by a person skilled in the art based on the embodiments of the present application, fall within the scope of protection of the present application.
X-ray diffraction instrument model: bruker D8 powder diffractometer;
measurement conditions: cu K alpha 1 lineMonochromatic radiation, 40kV and 40mA excitation.
Error value +/-0.2 DEG
The following examples will demonstrate the preparation and identification of novel crystalline forms of sodium supreme of the present application.
Example 1: preparation of sodium Shuganglucose crystals
The crude product of sodium sulmore gluconate is added into 13.2V of methanol and stirred for dispersion. Purified water was added for 2V dissolution. Stirring and heating the system to 70 ℃, cooling to 40-50 ℃ and keeping the temperature and stirring for 2 hours, wherein solids are just separated out from the system. Continuously cooling to 20-25 ℃, stirring and crystallizing for 2 hours, and filtering to obtain a solid. Eluting the filter cake with methanol 3V, drying at 80 ℃ in vacuum for 24 hours to obtain a solid, pulping the solid with ethanol 10V for 2 hours, filtering, eluting the filter cake with ethanol 3V, and drying at 80 ℃ in vacuum for 24 hours to obtain new crystal form alpha 1 crystals.
The diffraction angle of the alpha 1 crystal form is as follows:
| diffraction angle (2 theta) | Abundance (%) |
| 5.966 | 100.0 |
| 6.308 | 16.0 |
| 7.408 | 16.2 |
| 8.384 | 46.1 |
| 11.960 | 10.3 |
| 17.869 | 28.5 |
| 18.925 | 27.9 |
| 21.466 | 10.9 |
| 21.851 | 13.2 |
| 22.320 | 9.2 |
| 36.414 | 14.9 |
Example 2: preparation of sodium Shuganglucose crystals
And adding the sodium sugammadex crude product into 13.2V ethanol, and obtaining alpha 2 crystals which are also alpha crystal forms under the same conditions.
The diffraction angle of the alpha 2 crystal form is as follows:
example 3: preparation of sodium Shuganglucose crystals
The stirring temperature of the system is set to be raised to 60 ℃, and the rest conditions are unchanged, so that the alpha 3 crystal which is the alpha crystal form is obtained.
The diffraction angle of the alpha 3 crystal form is as follows:
example 4: preparation of sodium Shuganglucose crystals
The stirring temperature of the system is set to be raised to 80 ℃, and the rest conditions are unchanged, so that the alpha 4 crystal which is the alpha crystal form is obtained.
The diffraction angle of the alpha 4 crystal form is as follows:
example 5: preparation of sodium Shuganglucose crystals
The temperature is set to be reduced to 45 ℃, the solid is just separated out from the system, and the rest conditions are unchanged, so that the alpha 5 crystal which is also the alpha crystal form is obtained.
The diffraction angle of the alpha 5 crystal form is as follows:
comparative example 1: comparative preparation example
Adding 2V purified water into the sodium suger crude product for dissolution, stirring and heating the system to 70 ℃, dropwise adding 13.2V methanol to force out solid, then cooling to 20-25 ℃, stirring and crystallizing for 2 hours, and filtering to obtain the solid. Eluting the filter cake with methanol 3V, drying at 80 ℃ in vacuum for 24 hours to obtain a solid, pulping the solid with ethanol 10V for 2.0 hours, filtering, eluting the filter cake with ethanol 3V, and drying at 80 ℃ in vacuum for 24 hours to obtain beta crystals.
The diffraction angle of the beta crystal form is as follows:
comparative example 2: comparative preparation example
Adding 2V purified water into the sodium sugammadex crude product for dissolution, stirring and heating the system to 40-50 ℃, dropwise adding 13.2V methanol to force out solid, keeping the temperature and stirring for 2.0h, then cooling to 20-25 ℃, stirring and crystallizing for 2 h, and filtering to obtain solid. Eluting the filter cake with methanol 3V, drying at 80 ℃ in vacuum for 24 hours to obtain solid, pulping the solid with ethanol 10V for 2 hours, filtering, eluting the filter cake with ethanol 3V, and drying at 80 ℃ in vacuum for 24 hours to obtain gamma crystal.
The diffraction angle of the gamma crystal form is as follows:
comparative example 3: comparative preparation example
Adding purified water 2V to dissolve the crude product of the sodium sulfatase, adding the crude product of the sodium sulfatase into 13.2V of methanol, and stirring and dispersing the crude product of the sodium sulfatase. Stirring and heating the system to 70 ℃, directly cooling to 20-25 ℃, stirring and crystallizing for 2 hours, and filtering to obtain a solid. Eluting the filter cake with methanol 3V, drying at 80 ℃ in vacuum for 24 hours to obtain solid, pulping the solid with ethanol 10V for 2 hours, filtering, eluting the filter cake with ethanol 3V, and drying at 80 ℃ in vacuum for 24 hours to obtain theta crystal.
The diffraction angle of the theta crystal form is as follows:
depending on the synthetic route, sodium sulmore crystals exhibit different forms, namely the alpha, beta, gamma and theta forms, of which the alpha form (alpha 1 to alpha 5) is the most stable.
Example 6: stability study experiment of sodium Shuganglucose Crystal
Stability test data for sodium Shuganglucose crystals
The stability test is carried out on the sodium sugammadex crystal (alpha 1 crystal-alpha 5 crystal) manufactured by the application under the conditions of high temperature and illumination, and the content and the clarity of related substances are respectively observed on the 10 th day, the 30 th day and the 10 th day and the 30 th day under illumination at the high temperature of 0 ℃ and 60 ℃ and then the X-ray powder diffraction pattern is obtained by the crystal test.
(1) Alpha 1 crystalline sodium glycosurate crystal X-ray powder diffraction pattern when stability test is carried out under high temperature and illumination conditions:
/>
(2) Alpha 2 crystalline sodium glycosurate crystal X-ray powder diffraction pattern when stability test is carried out under high temperature and illumination conditions:
/>
(3) Alpha 3 crystal sodium gluconate crystal X-ray powder diffraction pattern when stability test is carried out under high temperature and illumination conditions:
/>
(4) Alpha 4 crystal sodium gluconate crystal X-ray powder diffraction pattern when stability test is carried out under high temperature and illumination conditions:
/>
(5) Alpha 5 crystal sodium gluconate crystal X-ray powder diffraction pattern when stability test is carried out under high temperature and illumination conditions:
/>
(6) Stability test under high temperature and illumination
Sample solutions were assayed for clarity by taking sodium sulmore prepared in examples 1 to 5 and comparative examples 1 to 3, respectively, and under conditions of 10 days high temperature 60 ℃, 10 days light, 30 days high temperature 60 ℃ and 30 days light. Referring to the registration standard of sodium sulmore injection (JX 20140183), the clarity detection of a sample solution refers to the "four-part rule of Chinese pharmacopoeia 2015". The results are shown in Table 1.
Table 1: clarity of the product
| Sample of | Day 0 | High temperature 60℃ for 10 days | 10 day illumination | High temperature 60℃ for 30 days | 30 days of illumination |
| Alpha 1 crystal form | Clarifying | Clarifying | Clarifying | Clarifying | Clarifying |
| Alpha 2 crystal form | Clarifying | Clarifying | Clarifying | Clarifying | Clarifying |
| Alpha 3 crystal form | Clarifying | Clarifying | Clarifying | Clarifying | Clarifying |
| Alpha 4 crystal form | Clarifying | Clarifying | Clarifying | Clarifying | Clarifying |
| Alpha 5 crystal form | Clarifying | Clarifying | Clarifying | Clarifying | Clarifying |
| Beta crystal form | Clarifying | Clarifying | Clarifying | Non-clarified (opacifying) | Non-clarified (opacifying) |
| Gamma crystal form | Clarifying | Clarifying | Clarifying | Non-clarified (opacifying) | Non-clarified (opacifying) |
| Theta crystal form | Clarifying | Clarifying | Clarifying | Non-clarified (opacifying) | Non-clarified (opacifying) |
(3) Under the stability test under high temperature and illumination, the contents of related substances are as follows:
table 2-1: alpha 1 crystal form
Table 2-2: alpha 2 crystal form
Table 2-3: alpha 3 crystal form
Tables 2 to 4: alpha 4 crystal form
Tables 2-5: alpha 5 crystal form
Tables 2-6: beta crystal form
Tables 2-7: gamma crystal form
Tables 2-8: theta crystal form
According to the X-ray powder diffraction patterns, tables 1 and 2-1 to 2-8, in the long-term high-temperature and light stability test, the sodium gluconate crystal disclosed by the application remains clear even after being subjected to light irradiation for 10 days to 30 days or at a high temperature of 60 ℃ for 10 days to 30 days, and the impurities are not obviously increased with time after being subjected to light irradiation for 10 days to 30 days or at a high temperature of 60 ℃ for 10 days to 30 days, so that the crystal disclosed by the application is particularly high-temperature and light stability for a long period of time. And related substances of the beta crystal form, the gamma crystal form and the theta crystal form have no alpha crystal form (alpha 1 crystal to alpha 5 crystal), so that the quality is good, and the continuous degradation trend is realized in the stability lofting process.
The embodiments of the present application have been described above with reference to the accompanying drawings, but the present application is not limited to the above-described embodiments, which are merely illustrative and not restrictive, and many forms may be made by those having ordinary skill in the art without departing from the spirit of the present application and the scope of the claims, which are to be protected by the present application.
Claims (10)
1. An alpha-crystalline form of sodium sugammadex characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ using Cu-Ka radiation, exhibiting characteristic peaks at 5.966,6.308,7.408,8.384, 11.960, 17.869, 18.925, 21.466, 21.851, 22.320, 36.414 degrees 2θ with an error value +/-0.2 °.
2. An alpha-crystalline form of sodium sugammadex characterized by the use of Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 5.965,6.269,7.405,8.405, 10.183, 11.976, 13.302, 13.975, 14.842, 15.770, 17.889, 18.314, 18.886, 20.284, 21.547, 21.850, 22.403, 23.902, 27.175, 29.962, 33.186 degrees of 2θ with an error value +/-0.2 °.
3. An alpha-crystalline form of sodium sugammadex characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ using Cu-Ka radiation, showing characteristic peaks at 2θ of 5.925,6.327,7.322,8.382,8.994, 10.068, 10.675, 11.877, 12.428, 13.292, 14.520, 15.618, 17.218, 17.870, 18.807, 19.107, 20.206, 21.808, 22.358, 23.942, 24.223, 25.806, 26.260, 27.111, 33.143 with an error value +/-0.2 °.
4. An alpha-crystalline form of sodium sugammadex characterized by the fact that, using Cu-Ka radiation, an X-ray powder diffraction pattern is obtained expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 2θ of 5.966,6.293,7.448,8.422, 10.109, 11.917, 13.306, 16.880, 17.888, 18.887, 20.290, 21.471, 21.812, 21.873, 23.840, 25.929, 33.351, 47.243 with an error value of +/-0.2 °.
5. An alpha-crystalline form of sodium sugammadex characterized by the use of Cu-Ka radiation to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, exhibiting characteristic peaks at 2θ of 5.559,5.967,6.348,7.349,8.404, 10.051, 10.761, 11.896, 13.302, 14.754, 15.669, 17.911, 18.805, 19.149, 20.265, 21.768, 22.377, 23.880, 24.040, 24.189, 26.885, 27.187, 29.533, 30.007, 38.456 with an error value of +/-0.2 °.
6. A process for the preparation of alpha-crystalline form of sodium comfort glucose as claimed in any one of claims 1 to 5,
step one: adding the sodium sugammadex crude product into a solvent, stirring and dispersing, adding purified water for dissolution, stirring and heating the system to 60-100 ℃, cooling to just precipitate solid in the system, keeping the temperature and stirring, continuously cooling to and stirring for crystallization, and filtering to obtain solid;
step two: and leaching the solid filter cake, drying in vacuum to obtain a solid, pulping and filtering the solid, leaching the filter cake, and drying in vacuum to obtain the novel crystal form alpha crystal.
7. The process according to claim 6, wherein the solvent is an alcoholic solvent, and preferably methanol.
8. The method according to claim 6, wherein in the first step, the temperature is raised to 65 ℃ to 80 ℃, the temperature is kept for 1.5 to 3 hours, more preferably the temperature is lowered to 30 ℃ to 60 ℃ when the solid is precipitated in the system, still more preferably the temperature is lowered to 40 ℃ to 50 ℃ when the solid is precipitated in the system.
9. The method according to claim 6, wherein the second condition is: and pulping the solid filter cake with ethanol for 1-2 hours, filtering, leaching the filter cake with ethanol, and drying at the temperature of 80-90 ℃ for 23-25 hours.
10. A pharmaceutical composition comprising sodium supreme glucose in the crystalline form of any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310679473.8A CN116606388B (en) | 2023-06-09 | 2023-06-09 | Alpha crystal form of sodium sugammadex and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310679473.8A CN116606388B (en) | 2023-06-09 | 2023-06-09 | Alpha crystal form of sodium sugammadex and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116606388A true CN116606388A (en) | 2023-08-18 |
| CN116606388B CN116606388B (en) | 2023-11-28 |
Family
ID=87679981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310679473.8A Active CN116606388B (en) | 2023-06-09 | 2023-06-09 | Alpha crystal form of sodium sugammadex and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116606388B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400182A (en) * | 2017-06-26 | 2017-11-28 | 江苏悦兴医药技术有限公司 | Relax more glucose sodium crystal A and its production and use |
| CN108929389A (en) * | 2017-05-23 | 2018-12-04 | 合肥博思科创医药科技有限公司 | A kind of environmentally protective easypro more glucose sodium preparation method |
| CN111040050A (en) * | 2019-12-26 | 2020-04-21 | 徐州工业职业技术学院 | Method for purifying sugammadex sodium |
| CN112538123A (en) * | 2019-09-20 | 2021-03-23 | 鲁南制药集团股份有限公司 | Crystal form M of sugammadex sodium |
| CN112538124A (en) * | 2019-09-20 | 2021-03-23 | 鲁南制药集团股份有限公司 | Crystal form of sugammadex sodium |
| CN114805639A (en) * | 2021-01-29 | 2022-07-29 | 北京澳合药物研究院有限公司 | Preparation method and application of high-purity sugammadex sodium |
| CN115505051A (en) * | 2018-06-22 | 2022-12-23 | 四川科伦药物研究院有限公司 | Method for refining sugammadex sodium |
-
2023
- 2023-06-09 CN CN202310679473.8A patent/CN116606388B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108929389A (en) * | 2017-05-23 | 2018-12-04 | 合肥博思科创医药科技有限公司 | A kind of environmentally protective easypro more glucose sodium preparation method |
| CN107400182A (en) * | 2017-06-26 | 2017-11-28 | 江苏悦兴医药技术有限公司 | Relax more glucose sodium crystal A and its production and use |
| CN115505051A (en) * | 2018-06-22 | 2022-12-23 | 四川科伦药物研究院有限公司 | Method for refining sugammadex sodium |
| CN112538123A (en) * | 2019-09-20 | 2021-03-23 | 鲁南制药集团股份有限公司 | Crystal form M of sugammadex sodium |
| CN112538124A (en) * | 2019-09-20 | 2021-03-23 | 鲁南制药集团股份有限公司 | Crystal form of sugammadex sodium |
| CN111040050A (en) * | 2019-12-26 | 2020-04-21 | 徐州工业职业技术学院 | Method for purifying sugammadex sodium |
| CN114805639A (en) * | 2021-01-29 | 2022-07-29 | 北京澳合药物研究院有限公司 | Preparation method and application of high-purity sugammadex sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116606388B (en) | 2023-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS6245576A (en) | Production of stable derivative of tracemide and diuretic containing stable torasemide | |
| CN112638873B (en) | Refining method of indocyanine green | |
| CN116606388B (en) | Alpha crystal form of sodium sugammadex and preparation method thereof | |
| CN102617575A (en) | Preparation process of high-purity oxymatrine | |
| WO2010039159A1 (en) | Thermally stable crystalline epirubicin hydrochloride | |
| WO2012077134A1 (en) | Process for preparing aripiprazole polymorphs | |
| CN111000803A (en) | Preparation process of clindamycin phosphate pharmaceutical composition for injection | |
| CN113336741B (en) | Rabeprazole sodium anhydride crystal form and preparation method thereof | |
| CN112724191B (en) | Refining method of dienogest | |
| CN102382007A (en) | Doxycycline hydrochloride compound and preparation method thereof | |
| KR101258430B1 (en) | Method for producing alpha form crystals of sapropterin hydrochloride | |
| CN104961751B (en) | A kind of Cefobutazine sodium compound and the pharmaceutical preparation containing the compound | |
| CN106478636A (en) | Ticagrelor crystal formation and preparation method | |
| CN102351828A (en) | Novel technology for extracting genistein | |
| CN114478575A (en) | Barosavirenz crystal form D and preparation method thereof | |
| CN110818816B (en) | Refining and crystallizing method of sugammadex sodium | |
| DE144634C (en) | ||
| CN109369425B (en) | Preparation method of fenofibric acid choline salt | |
| CN102432532B (en) | High-purity torasemide compound | |
| CN112094312B (en) | Crystal form A of cyclovirobuxine D dihydrochloride | |
| KR20120022940A (en) | NOVEL STABLE CRYSTAL OF 1-(2'-CYANO-2'-DEOXY-β-D-ARABINOFURANOSYL)CYTOSINE MONOHYDROCHLORIDE | |
| CN111574576B (en) | Refining method of diquafosol sodium | |
| CN110845407B (en) | Preparation method of chloroquinate crystal | |
| WO2015149638A1 (en) | Dabigatran etexilate mesylate crystalline form, preparation method and pharmaceutical composition thereof | |
| CN108690000A (en) | A kind of process for purification of avanaphil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |