CN104987287A - Preparation method for spherical ketoprofen lysine - Google Patents
Preparation method for spherical ketoprofen lysine Download PDFInfo
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- CN104987287A CN104987287A CN201510311676.7A CN201510311676A CN104987287A CN 104987287 A CN104987287 A CN 104987287A CN 201510311676 A CN201510311676 A CN 201510311676A CN 104987287 A CN104987287 A CN 104987287A
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- benzoylhydratropate
- lysine
- ketoprofen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- VHIORVCHBUEWEP-ZSCHJXSPSA-N [(5s)-5-amino-5-carboxypentyl]azanium;2-(3-benzoylphenyl)propanoate Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 VHIORVCHBUEWEP-ZSCHJXSPSA-N 0.000 title abstract 5
- 229960003059 ketoprofen lysine Drugs 0.000 title abstract 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 75
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims abstract description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000004472 Lysine Substances 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 229960000991 ketoprofen Drugs 0.000 claims abstract description 30
- 239000012046 mixed solvent Substances 0.000 claims abstract description 22
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 18
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 239000012296 anti-solvent Substances 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 20
- 229930182817 methionine Natural products 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
- 238000005352 clarification Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000005516 engineering process Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000001914 filtration Methods 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 2
- 238000001035 drying Methods 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 239000002245 particle Substances 0.000 description 6
- 238000009826 distribution Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 241000276425 Xiphophorus maculatus Species 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- -1 preferred Chemical compound 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method for spherical ketoprofen lysine. The method comprises the following steps that 1, ketoprofen is dissolved in methyl alcohol, heating is performed to enable the ketoprofen to be completely dissolved, lysine of the same molar equivalent is added to be reacted with the ketoprofen at room temperature, and filtering is performed to obtain a clear reaction solution; 2, anti solvent is evenly and dropwise added in the reaction solution at low temperature, and the anti solvent is mixed solvent of acetonitrile, ethyl acetate and isopropyl acetate or mixed solvent of acetonitrile and ethyl acetate or mixed solvent of acetonitrile and isopropyl acetate; 3, heat preservation crystallization is performed for 1-10 hours at low temperature; 4, filtering and drying are performed, and then the spherical ketoprofen lysine is prepared. According to the preparation method for the spherical ketoprofen lysine, the problems that in current industrial production, the requirement for equipment is rigorous, the product stability is poor, and the yield is low are effectively solved, the prepared spherical ketoprofen lysine has the advantages of being good in stability, liquidity and dispersity, and strong guarantee is supplied to the stable production of preparations; meanwhile, the technology operation is simple, and the method is suitable for the industrial production and has the high practical value.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, specifically a kind of spherical Lysine m-benzoylhydratropate preparation method.
Background technology
The features such as Ketoprofen BP 93 has anti-inflammatory, analgesia, antipyretic, and toxicity is low, and side effect is little, its antiinflammation is better than Ibuprofen BP/EP, is mainly used in the diseases such as treatment rheumatoid arthritis, rheumatic arthritis and gout.But Ketoprofen is water-soluble poor, have a strong impact on its bioavailability.
Lysine m-benzoylhydratropate, is also called Methionin Ketoprofen BP 93, is the double salt that Methionin and Ketoprofen BP 93 are formed.Lysine m-benzoylhydratropate has very strong water-soluble, not only can ensure the drug effect of Ketoprofen BP 93, and can greatly improve the water-soluble of Ketoprofen BP 93.The chemical structural formula of Lysine m-benzoylhydratropate is as follows:
。
China CN1939893A reports a kind of Lysine m-benzoylhydratropate preparation method, is be dissolved in water by Methionin, adds Ketoprofen BP 93, after clarification, by lyophilize, prepare Lysine m-benzoylhydratropate.The weak point of the method is, refrigerating process temperature is too low on the one hand, and general equipment cannot reach; Freezing time is long on the other hand, reduces working efficiency, improves production cost, be unfavorable for large-scale production; Meanwhile, poor by the product stability of refrigerating process gained, especially water absorbability can be stronger, not easily preserves.
China CN 103524365 reports a kind of preparation method of lysine-ketoprofen, and Methionin is dissolved in water by the method, after add Ketoprofen BP 93 salify, after reaction terminates, carry out dilution crystallization by dripping ethanol.Product yield prepared by the method is lower, and the less stable of products obtained therefrom, in atmosphere very easily moisture absorption, cannot preserve under normal temperature.
Summary of the invention
For solving the problems of the technologies described above, the invention provides one and prepare spherical Lysine m-benzoylhydratropate preparation method, the method is simple to operate, is easy to industrialization and controls, and stablizing of the product obtained is higher.
The present invention adopts following technical scheme: a kind of preparation method of spherical Lysine m-benzoylhydratropate, comprises the steps:
1) be dissolved in methyl alcohol by Ketoprofen BP 93, heating makes it dissolve completely, adds the Methionin of identical molar equivalent, room temperature reaction 1.5-4 hour; Filter clarification reaction solution;
2) under-20 ° of C ~ 10 ° C, evenly anti-solvent is dripped in the reaction solution that step 1) obtains, described anti-solvent is acetonitrile, ethyl acetate, the mixed solvent of the mixed solvent of the mixed solvent of isopropyl acetate or acetonitrile and ethyl acetate or acetonitrile and isopropyl acetate;
3) in step 2) temperature under, insulation crystallization 1 ~ 10 hour, is preferably 2 hours;
4) filter, dry, obtained spherical Lysine m-benzoylhydratropate.
Wherein, in step 1), Ketoprofen BP 93 is 1:2 ~ 1:10 with the ratio of methyl alcohol, is preferably 1:4.
Preferably, in step 1), anti-solvent is acetonitrile and isopropyl acetate mixed solvent, and acetonitrile is 1:10 ~ 10:1 with the ratio of the volume of isopropyl acetate, preferred, and acetonitrile is 1:1 with the ratio of the volume of isopropyl acetate.
HPLC >=95% of the Ketoprofen BP 93 raw material added in step 1), content >=95% of Methionin raw material.
Preferably, step 2) dropping temperature be-5 ° of C ~ 5 ° C.
Step 2) in the volume of anti-solvent and the ratio 2:1 ~ 20:1 of charging capacity, being preferably anti-solvent is 8:1 with the ratio of charging capacity.Charging capacity refers to Ketoprofen and Methionin quality sum.
Step 2) in the time for adding of anti-solvent be 1 ~ 5 hour, preferably, time for adding is 2 ~ 3 hours.
Step 1) and step 2) in the methyl alcohol, acetonitrile, ethyl acetate, the isopropyl acetate that use be technical grade.
Tool of the present invention has the following advantages:
1. can prepare particle diameter by present method is the spherical Lysine m-benzoylhydratropate particle of 20 order ~ 150 object, and this Particle Phase has mobility and preferably dispersiveness better for platy shaped particle.
2. the solid prepared by present method has stronger stability, and can deposit for some time in atmosphere can not moisture absorption, can be dry, packaging, stores and stable the providing of preparation ensures more effectively.
3. the temperature condition of present method reaction more easily reaches, simple to operate, lower to equipment requirements, be applicable to large-scale factory and amplify production, and preparation time is shorter, and be easy to industrialization and control, the quality of products obtained therefrom is higher, meets GMP and national requirements.
Accompanying drawing explanation
Fig. 1 is the microscope figure of the spherical Lysine m-benzoylhydratropate that embodiment 1 obtains;
Fig. 2 is the partial enlarged drawing of Fig. 1;
Fig. 3 is the size-grade distribution spectrogram of the spherical Lysine m-benzoylhydratropate that embodiment 1 obtains;
Fig. 4 is the DSC spectrogram of the spherical Lysine m-benzoylhydratropate that embodiment 1 obtains;
Fig. 5 is the spherical Lysine m-benzoylhydratropate TGA spectrogram that embodiment 1 obtains;
Fig. 6 is the XRPD spectrogram of the spherical Lysine m-benzoylhydratropate that embodiment 1 obtains.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further described, but protection scope of the present invention is not limited thereto.
Embodiment 1
50 g Ketoprofen BP 93 raw materials are added in 200 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2 hours.Be cooled to 5 ° of C, drip the mixed solvent be made up of 350mL acetonitrile and 350mL isopropyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 2 hours, filters, and dry, can obtain 68.32 g products, molar yield is 85.4%; HPLC=99.75%, single assorted≤0.05%, total assorted≤0.25%.
The microscope figure of the spherical Lysine m-benzoylhydratropate solid of the present embodiment acquisition of Fig. 1 display.Data as can be seen from microscope enlarged view, the Lysine m-benzoylhydratropate solid prepared by this method is the globular solids of radius about 20 μm.
Fig. 3 display be the particle size distribution figure of spherical Lysine m-benzoylhydratropate that the present embodiment obtains.From the results of grain size analysis of sample, the Lysine m-benzoylhydratropate even particle size distribution prepared by this method, presents good normal distribution.
Composition graphs 4, Fig. 5 and Fig. 6 are known: spherical Lysine m-benzoylhydratropate prepared by the present embodiment is unformed, are not crystal.
Embodiment 2
50 g Ketoprofen BP 93 raw materials are added in 400 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 1.5 hours.Be cooled to-5 ° of C, drip the mixed solvent be made up of 400mL acetonitrile and 600mL isopropyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 3 hours, filters, and dry, can obtain 67.04 g products, mass yield is 83.8%; HPLC=99.65%, single assorted≤0.10%, total assorted≤0.35%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 3
50 g Ketoprofen BP 93 raw materials are added in 500 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 3.5 hours.Be cooled to-10 ° of C, drip the mixed solvent be made up of 400mL acetonitrile and 600mL isopropyl acetate to reaction solution, time for adding is 3 hours, crystallization, growing the grain 3 hours, filters, and dry, can obtain 67.92 g products, mass yield is 84.9%; HPLC=99.6%, single assorted≤0.05%, total assorted≤0.40%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 4
50 g Ketoprofen BP 93 raw materials are added in 150 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 3.5 hours.Be cooled to-10 ° of C, drip the mixed solvent be made up of 600mL acetonitrile and 400mL ethyl acetate to reaction solution, time for adding is 3 hours, crystallization, growing the grain 5 hours, filters, and dry, can obtain 68.24 g products, mass yield is 85.3%; HPLC=99.70%, single assorted≤0.10%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 5
50 g Ketoprofen BP 93 raw materials are added in 200 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 4 hours.Be cooled to-15 ° of C, drip the mixed solvent be made up of 400mL acetonitrile and 600mL ethyl acetate to reaction solution, time for adding is 5 hours, crystallization, growing the grain 3 hours, filters, and dry, can obtain 68.52 g products, mass yield is 85.7%; HPLC=99.6%, single assorted≤0.05%, total assorted≤0.40%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 6
50 g Ketoprofen BP 93 raw materials are added in 200 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2.5 hours.Be cooled to-20 ° of C, drip the mixed solvent be made up of 600mL acetonitrile and 800mL ethyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 3 hours, filters, and dry, can obtain 67.44 g products, mass yield is 84.3%; HPLC=99.7%, single assorted≤0.05%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 7
50 g Ketoprofen BP 93 raw materials are added in 100 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2.5 hours.Be cooled to 0 ° of C, drip the mixed solvent be made up of 100mL acetonitrile and 1000mL ethyl acetate to reaction solution, time for adding is 5 hours, crystallization, growing the grain 1 hour, filters, and dry, can obtain 63.63 g products, mass yield is 79.5%; HPLC=99.7%, single assorted≤0.10%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 8
50 g Ketoprofen BP 93 raw materials are added in 100 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2.5 hours.Be cooled to 0 ° of C, drip the mixed solvent be made up of 1000 mL acetonitriles and 10 mL ethyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 10 hours, filters, and dry, can obtain 68.48 g products, mass yield is 85.6%; HPLC=99.7%, single assorted≤0.10%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 9
50 g Ketoprofen BP 93 raw materials are added in 100 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2.5 hours.Be cooled to 0 ° of C, drip the mixed solvent be made up of 80 mL acetonitriles and 80 mL ethyl acetate to reaction solution, time for adding is 1 hour, crystallization, growing the grain 2 hours, filters, and dry, can obtain 60.19 g products, mass yield is 75.2%; HPLC=99.7%, single assorted≤0.10%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 10
50 g Ketoprofen BP 93 raw materials are added in 100 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2.5 hours.Be cooled to 0 ° of C, drip the mixed solvent be made up of 1000 mL acetonitriles and 600 mL ethyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 10 hours, filters, and dry, can obtain 71.48 g products, mass yield is 89.4%; HPLC=99.1%, single assorted≤0.20%, total assorted≤0.90%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Embodiment 11
50 g Ketoprofen BP 93 raw materials are added in 200 mL methyl alcohol, is heated with stirring to clearly molten, adds the Methionin of equivalent, room temperature reaction 2 hours.Be cooled to 10 ° of C, drip the mixed solvent be made up of 350mL acetonitrile and 350mL isopropyl acetate to reaction solution, time for adding is 2 hours, crystallization, growing the grain 2 hours, filters, and dry, can obtain 66.5 g products, molar yield is 83.1%; HPLC=99.70%, single assorted≤0.10%, total assorted≤0.30%.
Can obtain through XRPD test and microscopic examination: the Lysine m-benzoylhydratropate that the present embodiment obtains also is be spherical design, and XRPD spectrogram and Fig. 4 are consistent.
Spherical Lysine m-benzoylhydratropate prepared by present method has good fluidity, good dispersity, the features such as stability is better, substantially non-hygroscopic after long period placement, for the quality stability of Lysine m-benzoylhydratropate provides safeguard, for the stably manufactured of preparation provides strong guarantee; Meanwhile, technological operation is simple, is applicable to suitability for industrialized production, has very strong practical value.
Claims (10)
1. a preparation method for spherical Lysine m-benzoylhydratropate, is characterized in that, comprises the steps:
1) be dissolved in methyl alcohol by Ketoprofen BP 93, heating makes it dissolve completely, adds the Methionin of identical molar equivalent, room temperature reaction 1.5-4 hour; Filter clarification reaction solution;
2) under-20 ° of C ~ 10 ° C, evenly anti-solvent is dripped in the reaction solution that step 1) obtains, described anti-solvent is acetonitrile, ethyl acetate, the mixed solvent of the mixed solvent of the mixed solvent of isopropyl acetate or acetonitrile and ethyl acetate or acetonitrile and isopropyl acetate;
3) in step 2) temperature under, insulation crystallization 1 ~ 10 hour;
4) filter, dry, obtained spherical Lysine m-benzoylhydratropate.
2. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, in step 1), Ketoprofen BP 93 is 1:2 ~ 1:10 with the ratio of methyl alcohol.
3. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, in step 1), anti-solvent is acetonitrile and isopropyl acetate mixed solvent, and acetonitrile is 1:10 ~ 10:1 with the ratio of the volume of isopropyl acetate.
4. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 3, is characterized in that, acetonitrile is 1:1 with the ratio of the volume of isopropyl acetate.
5. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, HPLC >=95% of the Ketoprofen BP 93 raw material added in step 1), content >=95% of Methionin raw material.
6. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, step 2) dropping temperature be-5 ° of C ~ 5 ° C.
7. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, step 2) in the ratio 2:1 ~ 20:1 of anti-solvent and charging capacity.
8. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, step 2) in the time for adding of anti-solvent be 1 ~ 5 hour.
9. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 8, is characterized in that, step 2) in the time for adding of anti-solvent be 2 ~ 3 hours.
10. the preparation method of a kind of spherical Lysine m-benzoylhydratropate according to claim 1, is characterized in that, step 1) and step 2) in the methyl alcohol, acetonitrile, ethyl acetate, the isopropyl acetate that use be technical grade.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748584A (en) * | 2016-11-29 | 2017-05-31 | 西南科技大学 | The method that emulsion method prepares spheroidization organic molecule monomer or compound |
| CN115038686A (en) * | 2019-12-23 | 2022-09-09 | 导博药物公司 | Ketoprofen eutectic, preparation thereof, pharmaceutical composition containing ketoprofen eutectic and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3508199A1 (en) * | 2018-01-05 | 2019-07-10 | Dompé farmaceutici S.p.A. | Immediate-release pharmaceutical compositions containing ketoprofen lysine salt |
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| CN1923798A (en) * | 2005-08-30 | 2007-03-07 | 陈亦林 | Preparation method of dexibuprofen amino acid salt and application |
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| CN106748584A (en) * | 2016-11-29 | 2017-05-31 | 西南科技大学 | The method that emulsion method prepares spheroidization organic molecule monomer or compound |
| CN115038686A (en) * | 2019-12-23 | 2022-09-09 | 导博药物公司 | Ketoprofen eutectic, preparation thereof, pharmaceutical composition containing ketoprofen eutectic and application thereof |
| CN115038686B (en) * | 2019-12-23 | 2024-04-30 | 导博药物公司 | Ketoprofen co-crystal and preparation thereof, pharmaceutical composition containing ketoprofen co-crystal and application thereof |
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| CN104987287B (en) | 2017-07-18 |
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