CN114478287A - Aspirin-lysine crystal form, preparation method and application - Google Patents
Aspirin-lysine crystal form, preparation method and application Download PDFInfo
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- CN114478287A CN114478287A CN202111672562.7A CN202111672562A CN114478287A CN 114478287 A CN114478287 A CN 114478287A CN 202111672562 A CN202111672562 A CN 202111672562A CN 114478287 A CN114478287 A CN 114478287A
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- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicine crystal forms, and particularly discloses an aspirin-lysine crystal form, and a preparation method and application thereof. The crystal form of aspirin-lysine provided by the invention is prepared by the reaction of aspirin and DL-lysine, and the X-ray powder diffraction pattern of the crystal form is shown in figure 1. The beta crystal form aspirin lysine obtained by the invention has better stability than the existing alpha crystal form aspirin lysine, and the crystal form of the invention is adopted to prepare the medicine, thereby being beneficial to long-term storage and prolonging the validity period.
Description
Technical Field
The invention belongs to the technical field of medicine crystal forms, and particularly relates to an aspirin-lysine crystal form, and a preparation method and application thereof.
Background
Aspirin-DL-aspirin is the product of the complexation reaction between aspirin and DL-lysine, and is one kind of medicine for relieving pain, clearing away heat and resisting rheumatism.
The aspirin lysine injection is crystal form of aspirin lysine, and the original manufacturer is Sonofield-Anthrate France. Aspirin-DL-lysine is white solid powder, and the crystal form of the Aspirin-DL-lysine can influence the degradation of impurities in the medicine storage process, thereby influencing the effective period of the medicine. In view of this, the research on the crystal form of aspirin-lysine is of great significance.
Therefore, the invention aims to research the crystal form of aspirin-lysine to find a better crystal form and increase the medication selection of people.
Disclosure of Invention
The invention mainly solves the technical problem of providing an aspirin-lysine crystal form and a preparation method of the crystal form. The crystal form provided by the invention has better stability.
In order to solve the technical problems, in a first aspect, the invention provides a crystal form of aspirin-lysine, wherein the crystal form is prepared by reacting aspirin and DL-lysine, and the X-ray powder diffraction of the crystal form at an angle of 2 theta (unit degree) is as follows: diffraction peaks are found at 13.2 + -0.2, 14.8 + -0.2, 19.8 + -0.2 and 21.1 + -0.2.
Preferably, the X-ray powder diffraction pattern of the crystalline form is shown in fig. 1.
In a second aspect, the invention provides a preparation method of aspirin-lysine crystal form, which comprises the following steps:
(1) mixing aspirin-containing solution with DL-lysine aqueous solution for reaction to precipitate crystals;
(2) then adding an organic solvent into the reaction system, cooling to 15 +/-2 ℃, and carrying out heat preservation reaction for 2-4 h;
(3) then cooling to 0-5 ℃, and reacting for 0.5-1.5 h under heat preservation;
(4) and (3) carrying out solid-liquid separation on the reaction system, washing and drying the separated solid to obtain the aspirin-lysine crystal.
As a preferred embodiment of the present invention, the organic solvent is methanol or isopropanol.
In a preferred embodiment of the invention, in the step (1), the material molar ratio of aspirin to DL-lysine is (0.9-1.2): 1.0, preferably 1: 1.
As a preferred embodiment of the present invention, the aspirin-containing solution is an organic solvent solution of aspirin, and the organic solvent is methanol or isopropanol.
In a preferred embodiment of the present invention, the reaction temperature of the mixing reaction in step (1) is 25 to 40 ℃, preferably 28 to 32 ℃.
In a preferred embodiment of the present invention, the reaction time of the mixing reaction in step (1) is 0.5 to 4 hours, preferably 2 hours.
In a preferred embodiment of the present invention, after the organic solvent is added in step (2), the weight ratio of the organic solvent to water in the reaction system is (5.0-10.0): 1.0, preferably (7.0-8.0): 1.0.
in a third aspect, the invention provides application of a crystal form of aspirin-lysine, wherein the crystal form is preferably applied to preparation of anti-inflammatory or analgesic drugs.
In a fourth aspect, the present invention also provides a medicament comprising the crystalline form; preferably, the medicament is in an injectable dosage form.
The crystal form of the aspirin lysine adopted by the aspirin lysine injection of the Sonofu-Antont company of original research manufacturer is analyzed, and the crystal form is found to be the crystal form alpha named in the invention. In the research on the crystal form of aspirin lysine, it was surprisingly found that different aspirin crystal form drugs can be prepared by a specific method, and a new crystal form (hereinafter referred to as beta crystal form) of aspirin lysine is obtained.
The physicochemical property of beta crystal form aspirin lysine obtained by the invention is not much different from that of the existing alpha crystal form aspirin lysine on the market, but the stability is superior to that of the alpha crystal form aspirin lysine, so that the crystal form of the invention is adopted to prepare a medicament, which is beneficial to long-term storage and prolongs the validity period.
The beta crystal form of aspirin-lysine prepared by the invention can be applied to the field of medicines, and a new choice is added for human medicine application.
Drawings
FIG. 1 is a PXRD test pattern for the beta crystalline form prepared in example 1 of the present invention;
FIG. 2 is a PXRD test pattern obtained for comparative example 1 of the present invention for the alpha crystalline form;
FIG. 3 is a PXRD test pattern for a reference formulation;
FIG. 4 is a PXRD test pattern for glycine.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to the specific embodiments. It will be understood by those skilled in the art that the embodiments described below are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. All other embodiments, such as modifications and substitutions, which can be obtained by one skilled in the art based on the embodiments of the present invention without any inventive step, belong to the protection scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the raw materials, reagents, instruments and the like used are commercially available unless otherwise specified.
Example 1
The embodiment provides an aspirin lysine beta crystal form, which comprises the following preparation steps:
adding 18.0g (0.1mol) of aspirin and 120.0g of methanol into a reaction bottle, stirring and dissolving at 28-32 ℃, dropwise adding 58.4g (0.1mol) of DL-lysine aqueous solution (with the mass percentage concentration of 25.0%) after dissolving, keeping the temperature at 28-32 ℃ after dropwise adding, reacting for 2 hours, and separating out a large amount of crystals; then 230g of methanol is dripped, the temperature is reduced to 15 +/-2 ℃ after dripping, and the temperature is kept for 3.0 h; then cooling to 0-5 ℃, and preserving heat for 1 h. Filtering, washing a filter cake with methanol, and drying damp products obtained by washing at 45-55 ℃ in vacuum to constant weight to obtain the white crystal 26.0g (0.79mol) of the aspirin lysine with the yield of 79.8%.
Through detection, the aspirin content in the aspirin-lysine crystal is 53.5% by mass, and the free salicylic acid content in the aspirin-lysine crystal is 0.09% by mass. PXRD test confirms that the crystal form is beta.
Example 2
The embodiment provides an aspirin lysine beta crystal form, which comprises the following preparation steps:
adding 18.0g (0.1mol) of aspirin and 120.0g of isopropanol into a reaction bottle, stirring and dissolving at 28-32 ℃, dropwise adding 58.4g (0.1mol) of DL-lysine aqueous solution (with the mass percentage concentration of 25.0%) after dissolving, keeping the temperature at 28-32 ℃ for reaction for 2 hours after completing dropwise adding, and separating out a large amount of crystals; then dripping 230g of isopropanol, cooling to 15 +/-2 ℃ after dripping, and preserving heat for 3.0 h; then cooling to 0-5 ℃, and preserving heat for 1 h. Filtering, washing a filter cake with isopropanol, and drying a damp product obtained by washing at 45-55 ℃ in vacuum to constant weight to obtain 28.5g (0.87mol) of aspirin-lysine white crystals with the yield of 87.4%.
Through detection, the aspirin content in the aspirin-lysine crystal is 53.8% by mass, and the free salicylic acid content in the aspirin-lysine crystal is 0.07% by mass. PXRD test confirms that the crystal form is beta.
Comparative example 1
The comparative example provides an aspirin lysine alpha crystal form, and the preparation steps are as follows:
adding 18.0g (0.1mol) of aspirin and 100.0g of acetone into a reaction bottle, stirring and dissolving at 30 +/-2 ℃, dropwise adding 58.4g (0.1mol) of DL-lysine aqueous solution (with the mass percentage concentration of 25.0%) after dissolving, and keeping the temperature at 30 +/-2 ℃ for reaction for 2 hours after finishing dripping, wherein a large amount of crystals are separated out; then 80g of acetone is dripped, and the temperature is reduced to 15 +/-2 ℃ after dripping, and is kept for 3.0 h; then cooling to 0-5 ℃, and preserving heat for 1 h. Filtering, washing a filter cake with acetone, and drying damp products obtained by washing at 45-55 ℃ in vacuum to constant weight to obtain 26.7g (0.82mol) of aspirin-lysine white crystals with the yield of 82.0%.
Through detection, the aspirin content in the aspirin-lysine crystal is 53.4% by mass, and the free salicylic acid content in the aspirin-lysine crystal is 0.12% by mass. PXRD test confirms alpha crystal form.
The PXRD test pattern for the beta crystalline form obtained in example 1 is shown in fig. 1, and the PXRD test pattern for the alpha crystalline form obtained in comparative example 1 is shown in fig. 2. The number of alpha crystal form and beta crystal form characteristic peaks and the absorption intensity at different crystal face angles are different.
Further, the aspirin-lysine injection preparation was used as a reference preparation (lot number GY303, seinuffield, the aspirin-lysine injection preparation was a mixture of aspirin-lysine and glycine), and the PXRD pattern of the reference preparation was shown in fig. 3, and the PXRD pattern of glycine was shown in fig. 4. The aspirin-lysine in the reference preparation can be confirmed to be in the alpha crystal form by deducting the corresponding crystal form peak of the PXRD crystal form from the PXRD crystal form of the reference preparation.
The crystal form stability of the alpha crystal form compound and the beta crystal form compound prepared by the method is compared and investigated. And carrying out stability comparison investigation on alpha crystal form aspirin lysine and beta crystal form aspirin under the same condition, and confirming the stability of the two crystal forms.
Stability study protocol: taking 1 batch of alpha crystal form aspirin lysine and beta crystal form aspirin lysine samples respectively, and packaging according to a sample packaging mode on the market (aluminum can sealed packaging).
The stability examination conditions were: the temperature is 30 +/-2 ℃ and the humidity is 65 +/-5%.
The stability test times were 0 day, 30 days and 90 days.
The stability inspection indexes comprise characters, content, acidity, clarity and color of solution and free salicylic acid.
The method for detecting the corresponding indexes under the second Laipirin variety item of 2015 version Chinese pharmacopoeia is executed for stability investigation. The comparative investigation result of the crystal form stability of the obtained aspirin lysine is shown in Table 1.
TABLE 1
The comparative results in table 1 show that the detection data of the two crystal form products in 0 day are basically consistent, along with the extension of the investigation time, the acidity change of the alpha crystal form sample is large, the increase of the free salicylic acid value is obvious, the acidity and the free salicylic acid of the beta crystal form aspirin lysine sample are small, the beta crystal form is more stable than the alpha crystal form, the aspirin lysine crystal form is a crystal form with better stability, and the prepared pharmaceutical preparation is favorable for long-term storage.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A crystal form of aspirin-lysine, characterized in that the crystal form is prepared by reaction of aspirin and DL-lysine, and the X-ray powder diffraction of the crystal form at an angle of 2 theta (unit degree) is: diffraction peaks are found at 13.2 + -0.2, 14.8 + -0.2, 19.8 + -0.2 and 21.1 + -0.2.
2. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
3. The preparation method of crystalline form of aspirin-lysine according to claim 1 or 2, characterized in that said preparation method comprises the steps of:
(1) mixing aspirin-containing solution with DL-lysine aqueous solution for reaction to precipitate crystals;
(2) then adding an organic solvent into the reaction system, cooling to 15 +/-2 ℃, and carrying out heat preservation reaction for 2-4 h;
(3) then cooling to 0-5 ℃, and reacting for 0.5-1.5 h under heat preservation;
(4) and (3) carrying out solid-liquid separation on the reaction system, washing and drying the separated solid to obtain the aspirin-lysine crystal.
4. The method according to claim 3, wherein the organic solvent is methanol or isopropanol.
5. The preparation method according to claim 3 or 4, wherein the material molar ratio of aspirin to DL-lysine is (0.9-1.2): 1.0, preferably 1: 1.
6. The production method according to any one of claims 3 to 5, wherein the aspirin-containing solution is an organic solvent solution of aspirin, and the organic solvent is methanol or isopropanol.
7. The preparation method according to claim 6, wherein the reaction temperature of the mixing reaction is 25-40 ℃, preferably 28-32 ℃; and/or the reaction time of the mixing reaction is 0.5-4 h, preferably 2 h.
8. The preparation method according to any one of claims 3 to 7, wherein after the organic solvent is added in the step (2), the weight ratio of the organic solvent to water in the reaction system is (5.0-10.0): 1.0, preferably (7.0-8.0): 1.0.
9. use of the crystalline form of claim 1 or 2 or the crystalline form obtained by the preparation method of any one of claims 3 to 8 for the preparation of an anti-inflammatory or analgesic medicament.
10. A medicament comprising the crystalline form of claim 1 or 2 or a crystalline form obtained by the preparation process of any one of claims 3 to 8; preferably, the medicament is in an injectable dosage form.
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Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1078888A (en) * | 1992-05-22 | 1993-12-01 | 蚌埠市医药研究所实验药厂 | The manufacture method of aspisol |
| CN1468209A (en) * | 2000-07-18 | 2004-01-14 | Stable salts of o-acetylsalicyclic with basic amino acids | |
| CN101633624A (en) * | 2009-08-04 | 2010-01-27 | 蚌埠丰原医药科技发展有限公司 | Preparation method of improved di-lysine-aspirin |
| CN102503845A (en) * | 2011-09-28 | 2012-06-20 | 广州普星药业有限公司 | Preparation method of DL-lysine aspirin salt and application thereof |
| CN102993036A (en) * | 2011-09-10 | 2013-03-27 | 海南中化联合制药工业股份有限公司 | Preparation method of aspirin-DL-lysine sterile raw material |
| FR2992641A1 (en) * | 2012-06-28 | 2014-01-03 | Dipharma Francis Srl | Preparing lysine acetylsalicylate used as non-steroidal anti-inflammatory drug, comprises dissolving acetylsalicylic acid in alcoholic solvent and mixing alcoholic solution with aqueous solution with lysine monoacetate to obtain suspension |
| CN104744249A (en) * | 2013-12-31 | 2015-07-01 | 海口天行健药物研究有限公司 | Method for preparing stable salt of aspirin and alkaline amino acid |
| CN106674036A (en) * | 2016-12-22 | 2017-05-17 | 河南中医学院 | Method for synthesizing aspirin-dl-lysine through non-organic solvent method |
| CN110511156A (en) * | 2019-08-28 | 2019-11-29 | 广州普星药业有限公司 | A kind of preparation method of di-lysine-aspirin |
| CN112500306A (en) * | 2020-12-11 | 2021-03-16 | 佛山普正医药科技有限公司 | Synthesis method of aspirin-lysine |
| CN112552196A (en) * | 2020-11-23 | 2021-03-26 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspirin-lysine |
| CN112592286A (en) * | 2020-11-23 | 2021-04-02 | 蚌埠丰原医药科技发展有限公司 | Preparation method of complex of aspirin and basic amino acid |
| CN113105326A (en) * | 2021-03-24 | 2021-07-13 | 海南卓华制药有限公司 | Preparation method and application of aspirin lysine |
| CN114394910A (en) * | 2021-12-30 | 2022-04-26 | 蚌埠丰原医药科技发展有限公司 | Refining method of aspirin-lysine |
-
2021
- 2021-12-31 CN CN202111672562.7A patent/CN114478287A/en active Pending
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1078888A (en) * | 1992-05-22 | 1993-12-01 | 蚌埠市医药研究所实验药厂 | The manufacture method of aspisol |
| CN1468209A (en) * | 2000-07-18 | 2004-01-14 | Stable salts of o-acetylsalicyclic with basic amino acids | |
| CN101633624A (en) * | 2009-08-04 | 2010-01-27 | 蚌埠丰原医药科技发展有限公司 | Preparation method of improved di-lysine-aspirin |
| CN102993036A (en) * | 2011-09-10 | 2013-03-27 | 海南中化联合制药工业股份有限公司 | Preparation method of aspirin-DL-lysine sterile raw material |
| CN102503845A (en) * | 2011-09-28 | 2012-06-20 | 广州普星药业有限公司 | Preparation method of DL-lysine aspirin salt and application thereof |
| FR2992641A1 (en) * | 2012-06-28 | 2014-01-03 | Dipharma Francis Srl | Preparing lysine acetylsalicylate used as non-steroidal anti-inflammatory drug, comprises dissolving acetylsalicylic acid in alcoholic solvent and mixing alcoholic solution with aqueous solution with lysine monoacetate to obtain suspension |
| CN104744249A (en) * | 2013-12-31 | 2015-07-01 | 海口天行健药物研究有限公司 | Method for preparing stable salt of aspirin and alkaline amino acid |
| CN106674036A (en) * | 2016-12-22 | 2017-05-17 | 河南中医学院 | Method for synthesizing aspirin-dl-lysine through non-organic solvent method |
| CN110511156A (en) * | 2019-08-28 | 2019-11-29 | 广州普星药业有限公司 | A kind of preparation method of di-lysine-aspirin |
| CN112552196A (en) * | 2020-11-23 | 2021-03-26 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspirin-lysine |
| CN112592286A (en) * | 2020-11-23 | 2021-04-02 | 蚌埠丰原医药科技发展有限公司 | Preparation method of complex of aspirin and basic amino acid |
| CN112500306A (en) * | 2020-12-11 | 2021-03-16 | 佛山普正医药科技有限公司 | Synthesis method of aspirin-lysine |
| CN113105326A (en) * | 2021-03-24 | 2021-07-13 | 海南卓华制药有限公司 | Preparation method and application of aspirin lysine |
| CN114394910A (en) * | 2021-12-30 | 2022-04-26 | 蚌埠丰原医药科技发展有限公司 | Refining method of aspirin-lysine |
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