CN103804184A - Novel crystal form of arginine ketoprofen and preparation method thereof - Google Patents
Novel crystal form of arginine ketoprofen and preparation method thereof Download PDFInfo
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- CN103804184A CN103804184A CN201410051053.6A CN201410051053A CN103804184A CN 103804184 A CN103804184 A CN 103804184A CN 201410051053 A CN201410051053 A CN 201410051053A CN 103804184 A CN103804184 A CN 103804184A
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- arginine
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- ketoprofen
- ketoprofenate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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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
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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
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Abstract
The invention provides a novel crystal form of arginine ketoprofen and a preparation method thereof, and particularly provides a crystal form A of arginine ketoprofen. The preparation method comprises steps of under the protection of nitrogen, sequentially adding ketoprofen and arginine into a solvent, heating up till the reaction liquid is clear and stopping heating, slowly cooling down, then crystallizing, and filtering the crystal so as to obtain the crystal form A of arginine ketoprofen, wherein the solvent comprises methyl alcohol and a solvent B, and the solvent B is one or more of isopropanol, ethylene glycol, ethyl ether, petroleum ether, cyclohexane, dichloromethane, trichloromethane, acetone, ethyl acetate and tetrahydrofuran. The crystal form A of arginine ketoprofen has good solubility and stability, and is obviously superior to the existing arginine ketoprofen solid.
Description
Technical field
The invention provides a kind of new crystal of arginine ketoprofenate, relate to pharmaceutical technology field.
Background technology
Arginine ketoprofenate is Ketoprofen arginic acid salt, has anti-inflammatory, analgesic activity.Arginine ketoprofenate has not only kept the drug effect of Ketoprofen, and change that it is water insoluble, make it have very outstanding water-soluble, make it can make powder injection, improve drug effect, reduced dosage, reduced GI hormesis, increase route of administration, expanded the clinical application of Ketoprofen.
The production technique of the disclosed arginine ketoprofenate of CN1376670A mainly adopts lyophilization, in reaction flask, add successively Ketoprofen, L-arginine and distilled water, stir to clarify, temperature-gradient method vacuum lyophilization from-40 degrees Celsius, obtains white solid arginine ketoprofenate.Its shortcoming is: 1, the temperature of freeze-drying is too low, vacuum tightness require high, to equipment require high, increase production cost; 2, the product that lyophilization obtains, owing to there is no purge process in production process, can make impurity pile up in product, and product porous, and color is partially dark, has ferocious water absorbability; 3, batch output that lyophilization is produced is less, is not suitable for suitability for industrialized production.
CN101935293A discloses a kind of method of preparing arginine ketoprofenate, is under aseptic condition, and Ketoprofen is dissolved in ethanolic soln, adds arginine powder after heating, reacts to solution clarification, obtains arginine ketoprofenate after decrease temperature crystalline.The method complexity that feeds intake adds arginine powder under heated condition, has the possibility of unexpected bumping, has certain potential safety hazard.
The arginine ketoprofenate production technique of prior art, there is certain problem in the arginine ketoprofenate stability making, is unfavorable for the clinical use of arginine ketoprofenate.Therefore provide that a kind of to prepare the method for stablizing arginine ketoprofenate be very necessary.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of method of stablizing arginine ketoprofenate of preparing, and obtain a kind of new arginine ketoprofenate crystal formation, described arginine ketoprofenate new crystal is called arginine ketoprofenate crystal form A, the present invention find unexpectedly this crystal form A except have good water-soluble, also there is excellent stability.The present invention also provides the production technique of this stable arginine ketoprofenate new crystal.
Technical solution of the present invention is as follows:
The invention provides a kind of arginine ketoprofenate crystal form A, it is characterized in that, in the X-ray powder diffraction of described crystal form A, 2 θ characteristic peaks are 5.26 ± 0.1 °, 11.55 ± 0.1 °, 11.88 ± 0.1 °, 13.04 ± 0.1 °, 15.86 ± 0.1 °, 19.12 ± 0.1 °, 20.08 ± 0.1 °, 20.40 ± 0.1 °, 21.34 ± 0.1 °, 22.42 ± 0.1 °, 23.22 ± 0.1 °, 24.00 ± 0.1 °, 24.62 ± 0.1 °, 27.4 ± 0.1 °, 32.42 ± 0.1 °, 34.48 ± 0.1 °.
The present invention also provides the method for arginine ketoprofenate crystal form A described above; it is characterized in that comprising the steps: under nitrogen protection; successively Ketoprofen and arginine are joined in solvent; be heated to reaction solution clarification; stop heating; crystallization after slow cooling; leaching crystal and get final product; wherein said solvent is made up of first alcohol and solvent B, and described solvent B is selected from Virahol, ethylene glycol, ether, sherwood oil, hexanaphthene, methylene dichloride, trichloromethane, acetone, ethyl acetate and tetrahydrofuran (THF) one or more.
Wherein, method described above, wherein said solvent B is preferably Virahol, sherwood oil, methylene dichloride, acetone or ethyl acetate.
Preferably, the method that the present invention is described above, wherein said solvent is by first alcohol and solvent B 1:(1～3 by volume) form particular methanol and solvent B 4:6 by volume.
Preferably, in the present invention's method described above, the consumption of wherein said solvent and Ketoprofen weight ratio are 2～6:1, are preferably 3:1.
Preferably, in the present invention's method described above, wherein Ketoprofen and arginine mol ratio are 1～1.1:1, are preferably 1:1.
Preferably, in the present invention's method described above, wherein the temperature of heating is 40～80 degrees Celsius, is preferably 60 degrees Celsius.
Preferably, in the present invention's method described above, wherein recrystallization temperature keeps 0 to room temperature, is preferably room temperature.
Preferably, in the present invention's method described above, wherein the time of reaction heating is 0.5-3 hour, is preferably 1 hour.
Preferably, in the present invention's method described above, wherein temperature fall time is 2-4 hour, is preferably 4 hours.
Preferably, in the present invention's method described above, the crystal of the arginine ketoprofenate crystal form A of wherein separating out, after leaching, through vacuum-drying, preferred vacuum drying vacuum tightness is 400-1000Pa, and drying temperature is 40-50 degree Celsius, and be 5-7 hour time of drying.
The present invention also provides a kind of pharmaceutical composition, and it is made up of arginine ketoprofenate crystal form A described above and pharmaceutically acceptable carrier, the arginine ketoprofenate crystal form A that this pharmaceutical composition contains significant quantity, for example in unit formulation, containing arginine ketoprofenate crystal form A is 0.01～500 milligram, wherein preferably comprises 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100,200,500 milligrams etc.Described carrier is not particularly limited, and can need to use according to formulation auxiliary material or the carrier of pharmaceutics routine, wherein comprises lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, N.F,USP MANNITOL, Sorbitol Powder, ethanol, glycerine, water etc.The formulation of pharmaceutical composition of the present invention is not particularly limited, for example, can be tablet, pill, and capsule, powder, particle, sterile solution or suspension, metered aerosol or fluid spray agent, drops, peace is cutd open, from injection or suppository etc.
The arginine ketoprofenate crystal form A that the present invention is described above, has kept the drug effect of Ketoprofen, has anti-inflammatory, and analgesic activity, can be prepared into anti-inflammatory or analgesic.
In the present invention's method described above, wherein said Ketoprofen is left-handed Ketoprofen, dexketoprofen or racemization Ketoprofen; Described arginine is L-arginine, D-Arg or DL-arginine.
The crystalline structure of arginine ketoprofenate crystal form A of the present invention is different from the arginine ketoprofenate that CN1376670A makes.In X-ray powder diffraction, the prepared arginine ketoprofenate crystal form A of the present invention has obvious characteristic peak, and the prepared arginine ketoprofenate of CN1376670A is without characteristic peak, shows that it is amorphous solid.
The crystalline structure of arginine ketoprofenate crystal form A of the present invention is also different from the arginine ketoprofenate that CN101935293A makes.In X-ray powder diffraction, there is obvious difference in the two, has diverse 2 θ characteristic peaks, illustrates that the two is diverse crystal formation.
Arginine ketoprofenate crystal form A of the present invention very easily dissolves in water and methyl alcohol, suitable with the prepared arginine ketoprofenate solvability of CN101935293A with CN1376670A.
Draw moist test according to 2010 editions pharmacopeia, drawing of the arginine ketoprofenate that the arginine ketoprofenate crystal form A that the mensuration embodiment of the present invention 1 makes, the arginine ketoprofenate that CN1376670A makes and CN101935293A make is moist, result arginine ketoprofenate crystal form A of the present invention draws wet weightening finish 0.9%, moist for slightly drawing, obviously be better than the arginine ketoprofenate that CN101935293A makes and (draw wet weightening finish 4.1%, performance have draw moist) and the obtained arginine ketoprofenate of CN1376670A (drawing wet weightening finish 20%, show very easily draw moist).
Accompanying drawing explanation
The X-ray powder diffraction figure of the arginine ketoprofenate crystal form A that Fig. 1: embodiment 1 makes
The X-ray powder diffraction figure of the arginine ketoprofenate that Fig. 2: CN1376670A makes
The X-ray powder diffraction figure of the arginine ketoprofenate that Fig. 3: CN101935293A makes
Embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but be not used for limiting the scope of the invention.Embodiment 1
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/isopropanol solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 37.83g, yield is 88.28%.
Embodiment 2
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methyl alcohol/petroleum ether solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 34.55g, yield is 80.63%.
Embodiment 3
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/dichloromethane solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 30.72g, yield is 71.69%.
Embodiment 4
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/acetone solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 32.62g, yield is 76.13%.
Embodiment 5
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/ethyl acetate solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 32.77g, yield is 76.48%.
Reference examples:
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins in 50.8ml methyl alcohol; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; add crystal seed, stirring and crystallizing 48 hours, filters; filter cake is at 50 degrees Celsius; vacuum tightness is 400Pa, under condition, and vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 5.44g, yield is 12.70%.
The arginine ketoprofenate solid phase prod that above embodiment 2-5 and reference examples make, X-ray powder diffraction after measured, all has 2 θ characteristic peaks in X-ray powder diffraction as identical in embodiment 1, has all obtained identical arginine ketoprofenate crystal form A.
Claims (10)
1. an arginine ketoprofenate crystal form A, is characterized in that, in the X-ray powder diffraction of described crystal form A, 2 θ characteristic peaks are 5.26 ± 0.1 °, 11.55 ± 0.1 °, 11.88 ± 0.1 °, 13.04 ± 0.1 °, 15.86 ± 0.1 °, 19.12 ± 0.1 °, 20.08 ± 0.1 °, 20.40 ± 0.1 °, 21.34 ± 0.1 °, 22.42 ± 0.1 °, 23.22 ± 0.1 °, 24.00 ± 0.1 °, 24.62 ± 0.1 °, 27.4 ± 0.1 °, 32.42 ± 0.1 °, 34.48 ± 0.1 °.
2. prepare the method for arginine ketoprofenate crystal form A claimed in claim 1 for one kind; it is characterized in that comprising the steps: under nitrogen protection; successively Ketoprofen and arginine are joined in solvent; be heated to reaction solution clarification; stop heating; crystallization after slow cooling; leaching crystal and get final product; wherein said solvent is made up of first alcohol and solvent B, and described solvent B is selected from Virahol, ethylene glycol, ether, sherwood oil, hexanaphthene, methylene dichloride, trichloromethane, acetone, ethyl acetate and tetrahydrofuran (THF) one or more.
3. method according to claim 2, wherein said solvent B is preferably Virahol, sherwood oil, methylene dichloride, acetone or ethyl acetate.
4. according to the method described in claim 2-3, wherein said solvent is by first alcohol and solvent B 1:(1～3 by volume) form particular methanol and solvent B 4:6 by volume.
5. according in the method described in claim 2-4, the consumption of wherein said solvent and Ketoprofen weight ratio are 2～6:1.
6. according in the method described in claim 2-5, wherein Ketoprofen and arginine mol ratio are 1～1.1:1.
7. according in the method described in claim 2-6, wherein the temperature of heating is 40～80 degrees Celsius.
8. according in the method described in claim 2-7, wherein recrystallization temperature keeps 0 to room temperature, is preferably room temperature.
9. a pharmaceutical composition, it is made up of arginine ketoprofenate crystal form A claimed in claim 1 and pharmaceutically acceptable carrier.
10. arginine ketoprofenate crystal form A claimed in claim 1 is in the application of preparing in anti-inflammatory or analgesic.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410051053.6A CN103804184B (en) | 2014-02-14 | 2014-02-14 | The crystal formation of arginine ketoprofenate and preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409217A (en) * | 2020-12-07 | 2021-02-26 | 江苏优普生物化学科技股份有限公司 | Preparation process of arginine ketone |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5665384A (en) * | 1990-04-06 | 1997-09-09 | Rhone-Poulenc Rorer S.A. | Oily capsules of ketoprofen |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
| CN1767824A (en) * | 2003-03-18 | 2006-05-03 | 德国柏林开米艾克泰尼盖塞尔查福特联合股份公司 | Photostabilized topical formulations of KETOPROFEN |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
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2014
- 2014-02-14 CN CN201410051053.6A patent/CN103804184B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5665384A (en) * | 1990-04-06 | 1997-09-09 | Rhone-Poulenc Rorer S.A. | Oily capsules of ketoprofen |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
| CN1767824A (en) * | 2003-03-18 | 2006-05-03 | 德国柏林开米艾克泰尼盖塞尔查福特联合股份公司 | Photostabilized topical formulations of KETOPROFEN |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409217A (en) * | 2020-12-07 | 2021-02-26 | 江苏优普生物化学科技股份有限公司 | Preparation process of arginine ketone |
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