CN113336757B - Preparation method of levofolinic acid crystal - Google Patents
Preparation method of levofolinic acid crystal Download PDFInfo
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- CN113336757B CN113336757B CN202110459488.4A CN202110459488A CN113336757B CN 113336757 B CN113336757 B CN 113336757B CN 202110459488 A CN202110459488 A CN 202110459488A CN 113336757 B CN113336757 B CN 113336757B
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Abstract
The invention relates to a preparation method of levofolinic acid crystals, which comprises the following steps: (1) adding amorphous levofolinic acid into an alcohol-water mixed solvent, and uniformly stirring and dispersing at 0-30 ℃ to obtain a levofolinic acid dispersion; the alcohol-water mixed solvent is a mixed solvent of methanol and/or ethanol and water; (2) adding alkali liquor into the levofolinic acid dispersion obtained in the step (1), adjusting the pH value of the levofolinic acid dispersion to 3.9-4.6, stirring and carrying out crystal transformation at the temperature of-20-35 ℃, separating out solids after crystal transformation, washing and drying to obtain levofolinic acid crystals. The related substances and the ignition residues of the levofolinic acid crystals prepared by the method completely meet the quality requirements of the injection preparation, the stability of the levofolinic acid crystals is high, the yield and the purity are high, the yield reaches 90 percent, the purity reaches 99 percent, and the ignition residues of the levofolinic acid crystals are less than 0.5 percent, so that the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of levofolinic acid crystals.
Background
Folic acid is a vitamin (vitamin B9) which cannot be synthesized by the human body, and after being absorbed by intestinal tracts, food rich in folic acid enters the liver and is converted under the action of dihydrofolate reductase to be transferred into one-carbon group tetrahydrofolic acid which is transferred in vivo and participates in the synthesis of purine and pyrimidine, so that the folic acid is an important raw material for the protein and cell division of the human body.
Stability of folic acid: water, estrogen, sulfa drugs, sunlight, food processing (especially boiling), high temperature and ultraviolet rays can cause the folic acid solution to lose activity, the alkaline solution of the folic acid is easily oxidized, and the acidic solution is unstable to heat, so that the folic acid needs to be shielded from light and stored hermetically. When the folic acid is insufficient, the antibody is continuously reduced, the resistance is gradually weakened, and the antibody not only influences hematopoietic cells to cause megaloblastic anemia, but also influences body cells such as digestive tract mucosal cells.
Calcium folinate is calcium salt of tetrahydrofolic acid formyl derivative, is activated form of folic acid in vivo, can be an antianemia drug and an auxiliary drug for resisting tumors, has toxic effect on timely acid antagonists (such as methotrexate, pyrimethamine and trimethoprim), and has the following structure:
the 6-position carbon atom is a chiral carbon atom, only the levorotatory body has biological activity, the dosage of the levorotatory calcium folinate is 1/2 of calcium folinate, products on the market at home and abroad at present comprise calcium folinate injection and calcium levofolinate injection, wherein calcium salt of the calcium levorotatory calcium folinate preparation has low water solubility and is not easy to prepare high-concentration preparation, on the other hand, the excessive calcium ion concentration in blood plasma can cause unnecessary side effects, so the calcium levorotatory calcium folinate is usually required to be slowly dripped, the usage dosage is limited, therefore, the levorotatory calcium folinate is prepared into sodium salt, the sodium levorotatory calcium folinate has good water solubility and biocompatibility, the drug effect and safety of the sodium levorotatory calcium folinate are obviously superior to the calcium folinate and the calcium levorotatory calcium folinate, and the sodium levorotatory calcium folinate has more advantages in clinical application. There are sodium levofolinate injection available from Huishan company of America and MEDAC company of Germany abroad.
Chinese patent CN101229167A, Chinese patent CN101780084A and CN102743331A all report that levofolinic acid is used as a raw material medicine to prepare a sodium salt form injection administration preparation, so that the quality of the raw material medicine levofolinic acid is crucial to the quality of the injection. The stability of the levofolinic acid is similar to that of folic acid, and the U.S. Pat. No. 3, 20080153849, 1 states that the levofolinic acid prepared by acidification is in an amorphous state, but the amorphous substance has poor stability, and needs to be stored under harsh conditions, so that the use cost is increased, and the shelf life of the raw material drug is influenced, therefore, in order to improve the stability of the levofolinic acid raw material drug, it is necessary to explore and prepare a stable levofolinic acid crystal, the current reports on the preparation research of the levofolinic acid crystal are few, and U.S. Pat. No. 20120245177 discloses a preparation method of crystalline levofolinic acid, and provides XRD spectrum analysis of the levofolinic acid crystalThe data shows that the levofolinic acid in the crystal form has the following characteristic peaks (2 theta value +/-0.2)0): 14.4, 17.3, 17.7, 18.3, 19.7, 20.0, 22.1, 23.3, 27.3. The levofolinic acid crystal with the crystal form has better performance in acceleration and long-term stability research, but the provided preparation method is harsh and complicated and is not beneficial to industrial production. In addition, as the levofolinic acid is prepared into an injection for a human body and has higher requirements on the levofolinic acid raw material medicine, the exploration of a preparation method suitable for industrially producing the high-quality levofolinic acid crystal with the crystal form is particularly important.
Disclosure of Invention
The invention aims to provide a method for preparing the levofolinic acid crystal by stirring and crystallizing amorphous levofolinic acid on the basis of the prior art, which has the advantages of simple preparation method, high yield and purity and suitability for large-scale production.
The technical scheme of the invention is as follows:
a preparation method of levofolinic acid crystals comprises the following steps:
(1) adding amorphous levofolinic acid into an alcohol-water mixed solvent, and uniformly stirring and dispersing at 0-30 ℃ to obtain a levofolinic acid dispersion; wherein the alcohol-water mixed solvent is a mixed solvent of methanol and/or ethanol and water;
(2) adding alkali liquor into the levofolinic acid dispersion obtained in the step (1), adjusting the pH value of the levofolinic acid dispersion to 3.9-4.6, stirring and carrying out crystal transformation at the temperature of-20-35 ℃, separating out solids after crystal transformation, washing and drying to obtain levofolinic acid crystals; wherein the alkali liquor is prepared from one or more of hydroxide, acetate or carbonate of alkaline earth metal and mixed solution of water and methanol or ethanol.
The levofolinic acid crystal prepared by the method of the invention has an XRD pattern as shown in figure 1.
For the present invention, when the crystalline levofolinic acid is prepared, amorphous levofolinic acid is used as the raw material, and various amorphous levofolinic acids prepared in the prior art, for example, amorphous levofolinic acid prepared by the method disclosed in patent CN 111138434A, can be used. The specific raw material can be amorphous levofolinic acid wet product, or dried amorphous levofolinic acid.
In order to overcome the defects in the process of preparing crystalline levofolinic acid disclosed in the US patent 20120245177, the invention takes high-quality amorphous levofolinic acid prepared by the conventional process in the prior art as a raw material, disperses the raw material in an alcohol-water mixed solvent at a proper temperature, adds alkali liquor, controls the pH value of the raw material, adopts the conventional stirring mode, and can obtain levofolinic acid crystals meeting the crystal form requirements through crystal transformation.
In the step (1), amorphous levofolinic acid is added into an alcohol-water mixed solvent, wherein the alcohol-water mixed solvent is a mixed solvent of methanol and/or ethanol and water, and can be a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of methanol, ethanol and water. In a preferable embodiment, the volume ratio of methanol and/or ethanol to water in the alcohol-water mixed solvent is 1: 1-6, but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6, and for better effect, the volume ratio of methanol and/or ethanol to water in the alcohol-water mixed solvent is 1: 3-5.
In a preferable embodiment, the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 3-100 kg/L, but not limited to 1:3kg/L, 1:4kg/L, 1:4.5kg/L, 1:6kg/L, 1:8kg/L, 1:10kg/L, 1:20kg/L, 1:40kg/L, 1:50kg/L, 1:70kg/L, 1:90kg/L or 1:100kg/L, and for better effect, the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 4-50 kg/L, and more preferably, the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 4.5-10 kg/L.
In the step (1), amorphous levofolinic acid is added into the alcohol-water mixed solvent, and stirred and dispersed uniformly at 0-30 ℃, wherein the stirring and dispersing temperature can be but is not limited to 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃ or 30 ℃, and can also be a temperature range, such as 0-20 ℃, 0-5 ℃, 0-10 ℃, 0-15 ℃ or 5-10 ℃. In order to obtain better effect, the temperature of stirring dispersion is 0-15 ℃, 0-5 ℃ or 5-10 ℃.
In the step (2), adding alkali liquor to the levofolinic acid dispersion obtained in the step (1) to adjust the pH value to 3.9-4.6, wherein the specific pH value can be but is not limited to 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5 or 4.6, and adding alkali liquor to adjust the pH value to 4.0-4.5, more preferably, adding alkali liquor to adjust the pH value to 4.1-4.2, in order to obtain higher yield and improve the purity of the levofolinic acid crystals.
In the step (2), the alkali liquor is prepared by mixing one or more of hydroxides, acetates or carbonates of alkaline earth metals with a mixed solution of water and methanol or ethanol. Among them, the alkaline earth metal may be, but is not limited to, metallic sodium or metallic potassium. In a preferred embodiment, the concentration of the alkali solution is 1% to 50%, and can be, but is not limited to, 1%, 5%, 10%, 15%, 20%, 30%, 40%, or 50%, and for better effect, the concentration of the alkali solution is 5% to 15%. The concentration of the lye refers to the percentage content of the hydroxides, acetates and/or carbonates of the alkaline earth metals.
When the alkaline earth metal is sodium, the alkali liquor is prepared from one or more of sodium hydroxide, sodium acetate or sodium carbonate, and mixed solution of water and methanol or ethanol. Preferably, the alkali liquor is prepared from a mixed solution of sodium hydroxide, water and methanol or ethanol, wherein the volume ratio of methanol or ethanol to water in the alkali liquor is 1: 1-6, but not limited to 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6, and further preferably, the volume ratio of methanol or ethanol to water in the alkali liquor is 1: 3-5. At this time, the concentration of the alkali solution is 5% to 15%, that is, the content of sodium hydroxide in the alkali solution is 5% to 15%.
In the step (2), alkali liquor is added into the levofolinic acid dispersion obtained in the step (1), the pH value is adjusted to 3.9-4.6, then stirring and crystal transformation are carried out at-20-35 ℃, the temperature of stirring and crystal transformation can be but not limited to-20 ℃, 10 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃ or 35 ℃, and can also be a temperature range, such as 0-35 ℃, 0-30 ℃, 0-20 ℃, 0-15 ℃, 0-5 ℃, 0-10 ℃, 5-15 ℃, 5-20 ℃ or 20-30 ℃. In a preferred scheme, the temperature for stirring and crystal transformation is 0-5 ℃, 0-10 ℃ or 5-10 ℃.
When the stirring is carried out for crystal transformation, the stirring mode can adopt an anchor type or a paddle type, and the paddle type stirring is preferred. The time for stirring and crystal transformation is 4-16 hours, but not limited to 4 hours, 6 hours, 8 hours, 10 hours, 12 hours or 16 hours, and for better effect, the time for stirring and crystal transformation is preferably 8-12 hours.
For the present invention, in the step (2), the solvent selected in the washing is one or more of water, methanol or ethanol; during drying, the drying mode is decompression freeze-drying, vacuum drying or blast drying, and the drying temperature is-20-30 ℃, preferably 10-30 ℃.
By adopting the technical scheme of the invention, the advantages are as follows:
according to the preparation method of the levofolinic acid crystal, amorphous levofolinic acid is used as a raw material and is dispersed in an alcohol-water mixed solvent, alkali liquor is added, the pH value of the raw material is controlled, and the crystal transformation is performed by adopting a conventional stirring mode to obtain the levofolinic acid crystal meeting the crystal form requirement. The related substances and the ignition residues of the levofolinic acid crystals prepared by the method completely meet the quality requirements of the injection preparation, the stability of the levofolinic acid crystals is high, the yield and the purity are high, the yield reaches 90 percent, the purity reaches 99 percent, and the ignition residues of the levofolinic acid crystals are less than 0.5 percent, so that the method is suitable for large-scale production.
Drawings
FIG. 1 is an XRD pattern of crystals of levofolinic acid prepared in example 1;
FIG. 2 is an XRD pattern of crystals of levofolinic acid prepared in example 2;
FIG. 3 is an XRD pattern of the crystals of levofolinic acid prepared in comparative example 1;
FIG. 4 is an XRD pattern of crystals of levofolinic acid prepared in comparative example 2;
FIG. 5 is an XRD pattern of crystals of levofolinic acid prepared in comparative example 3;
fig. 6 is an XRD pattern of the levofolinic acid crystal prepared in comparative example 6.
Detailed Description
The method for producing the crystal of the present invention is further illustrated by the following examples in conjunction with the drawings, but the present invention is not limited to these examples.
Example 1: preparation of levofolinic acid crystals
(1) Adding 45L of pure water into a 100L glass reaction kettle, heating to 55-60 ℃ under stirring, adding 1.5kg (2.45mol, 16.4% of water) of calcium levofolinate, keeping the temperature at 55-60 ℃, stirring to be basically dissolved, cooling to 0-10 ℃ firstly, dropwise adding a sodium carbonate aqueous solution (520.0g of sodium carbonate (4.9mol) is dissolved in 7.0L of pure water), keeping the temperature at 0-10 ℃, stirring for 1 hour under heat preservation, filtering out precipitated solids, washing a filter cake once with 200ml of pure water, and obtaining a filtrate, namely the sodium levofolinate solution. Putting the filtrate into a 100L glass reaction kettle, cooling to 0-5 ℃ under stirring, controlling the temperature of a reaction system to be 0-5 ℃, uniformly dropwise adding 1N dilute hydrochloric acid, stopping dropwise adding when the pH value of an acidification end point is 2.0-2.5, stirring for about 30min, standing and aging for 30min, filtering, washing a filter cake for 2 times by using 7.5L pure water, draining to obtain 4.5kg of amorphous levofolinic acid wet product, and drying to obtain 1.1kg of amorphous levofolinic acid.
(2) Adding 1.10kg of the amorphous levofolinic acid obtained in the step (1) into 5L of mixed solution of ethanol and water (the volume ratio of the ethanol to the water in the mixed solution is 1:5), and uniformly stirring and dispersing at the temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; dropwise adding a 5% sodium hydroxide ethanol aqueous solution (the volume ratio of ethanol to water in the ethanol aqueous solution is 1:5), adjusting the pH value to 4.10, stirring and crystallizing for 8 hours at the temperature of 5-10 ℃, filtering, washing the obtained solid once with 200ml of purified water and once with 200ml of ethanol, and drying the washed solid by blowing at the temperature of 10-30 ℃ to obtain 1.02kg of levofolinic acid crystals, wherein the yield is as follows: 92.7% (incandescence residue: 0.2%, XRD is shown in figure 1).
The levofolinic acid crystals obtained in example 1 were analyzed by high performance liquid chromatography to determine the purity of 99.6%, and the relevant experimental data are summarized in the following table 1:
TABLE 1 chromatographic data
| Peak number | Retention time | Area of | Height | Area% |
| 1 | 1.925 | 361 | 62 | 0.003 |
| 2 | 2.518 | 122 | 12 | 0.001 |
| 3 | 3.056 | 12269 | 1946 | 0.119 |
| 4 | 5.159 | 1878 | 148 | 0.018 |
| 5 | 6.208 | 1571 | 175 | 0.015 |
| 6 | 6.900 | 470 | 40 | 0.005 |
| 7 | 7.272 | 547 | 49 | 0.005 |
| 8 | 7.828 | 285 | 29 | 0.003 |
| 9 | 9.750 | 896 | 68 | 0.009 |
| 10 | 12.094 | 10221 | 587 | 0.099 |
| 11 | 13.882 | 1282 | 42 | 0.012 |
| 12 | 16.608 | 10286020 | 211373 | 99.588 |
| 13 | 25.736 | 12698 | 362 | 0.123 |
| Total of | 10328618 | 214851 | 100.000 |
Example 2: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into 3L of mixed solution of methanol and water (the volume ratio of methanol to water in the mixed solution is 1:5), and uniformly stirring and dispersing at the controlled temperature of 0-5 ℃ to obtain a levofolinic acid dispersion; dropwise adding 5% sodium hydroxide methanol aqueous solution (volume ratio of methanol to water in methanol aqueous solution is 1:5), adjusting pH to 4.20, stirring and crystallizing at 0-5 deg.C for 12 hr, filtering, washing the obtained solid with 100ml purified water, washing with 100ml methanol, vacuum drying at 10-30 deg.C to obtain 0.46kg levofolinic acid crystal, yield: 92% (purity: 99.54%, residue on ignition: 0.2%, XRD shown in figure 2).
Comparative example 1: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into 3L of mixed solution of isopropanol and water (the volume ratio of the isopropanol to the water in the mixed solution is 1:5), and uniformly stirring and dispersing at the controlled temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; dropwise adding a 5% sodium hydroxide isopropanol aqueous solution (volume ratio of isopropanol to water in the isopropanol aqueous solution is 1:5), adjusting the pH value to 4.10, stirring and carrying out crystal transformation for 8 hours at the temperature of 5-10 ℃, filtering, washing the obtained solid with 100ml of purified water, washing with 100ml of isopropanol once, and drying the washed solid by blowing at the temperature of 10-30 ℃ to obtain 0.43kg of levofolinic acid crystals, wherein the yield is as follows: 86% (purity: 99.44%, residue on ignition: 0.53%, XRD shown in figure 3).
As can be seen from fig. 3, the blunt peaks appearing at the positions 22.1 and 23.3 of the characteristic peak 2 θ may be incomplete in crystal transformation, and mixed crystals may exist. As can be seen from the stability data in Table 2, the content of impurity 10, impurity 6 and impurity 4 was significantly increased and the stability was poor after 12 months of storage of the crystals of levofolinic acid in this comparative example.
Comparative example 2: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into 5L of mixed solution of ethanol and water (the volume ratio of ethanol to water in the mixed solution is 1:5), and uniformly stirring and dispersing at the controlled temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; dropwise adding a 5% sodium hydroxide ethanol aqueous solution (the volume ratio of ethanol to water in the ethanol aqueous solution is 1:5), adjusting the pH value to 3.70, stirring and crystallizing for 8 hours at the temperature of 5-10 ℃, filtering, washing the obtained solid with 100ml of purified water once, then washing with 100ml of ethanol once, and drying the washed solid by blowing at the temperature of 10-30 ℃ to obtain 0.47kg of levofolinic acid crystals, wherein the yield is as follows: 94% (purity: 99.14%, residue on ignition: 0.18%, XRD shown in figure 4).
As can be seen from fig. 4, the occurrence of the blunt peak at the positions 22.1 and 23.3 of the characteristic peak 2 θ may be incomplete, and mixed crystals may exist. As can be seen from the stability data in Table 2, the content of impurity 10, impurity 6 and impurity 4 was significantly increased and the stability was poor after 12 months of storage of the crystals of levofolinic acid in this comparative example.
Comparative example 3: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into 5L of mixed solution of ethanol and water (the volume ratio of ethanol to water in the mixed solution is 3:1), and uniformly stirring and dispersing at the controlled temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; dropwise adding a 5% sodium hydroxide ethanol aqueous solution (the volume ratio of ethanol to water in the ethanol aqueous solution is 3:1), adjusting the pH value to 4.00, stirring and crystallizing for 8 hours at the temperature of 5-10 ℃, filtering, washing the obtained solid with 100ml of purified water once, then washing with 100ml of ethanol once, and drying the washed solid by blowing at the temperature of 10-30 ℃ to obtain 0.46kg of levofolinic acid crystals, wherein the yield is as follows: 92% (purity: 99.34%, residue on ignition: 0.68%, XRD shown in figure 5).
As can be seen from fig. 5, the occurrence of the blunt peak at the positions 22.1 and 23.3 of the characteristic peak 2 θ may be incomplete, and mixed crystals may exist. As can be seen from the stability data in Table 2, the content of impurity 10, impurity 6 and impurity 4 was significantly increased and the stability was poor after 12 months of storage of the crystals of levofolinic acid in this comparative example.
Comparative example 4: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into 5L of mixed solution of ethanol and water (the volume ratio of ethanol to water in the mixed solution is 1:5), and uniformly stirring and dispersing at the controlled temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; dropwise adding a 5% sodium hydroxide ethanol aqueous solution (the volume ratio of ethanol to water in the ethanol aqueous solution is 1:5), adjusting the pH value to 4.70, stirring and crystallizing for 8 hours at the temperature of 5-10 ℃, filtering, washing the obtained solid with 100ml of purified water once, then washing with 100ml of ethanol once, and drying the washed solid by blowing at the temperature of 10-30 ℃ to obtain 0.28kg of levofolinic acid crystals, wherein the yield is as follows: 56% (low yield, purity: 99.39%, residue on ignition: 0.15%).
Comparative example 5: preparation of levofolinic acid crystals
Adding 0.5kg of amorphous levofolinic acid into a mixed solution of 3L of ethanol and water (the volume ratio of ethanol to water in the mixed solution is 1:5), and uniformly stirring and dispersing at the controlled temperature of 5-10 ℃ to obtain a levofolinic acid dispersion; then 5% sodium hydroxide ethanol water solution (the volume ratio of ethanol to water in the ethanol water solution is 1:5) is dripped into the mixture, the pH value is adjusted to 5.0, and crystal transformation is carried out for 24 hours under the condition of 5-10 ℃, and few crystals are separated out in the crystal transformation process.
Comparative example 6: preparation of crystals of levofolinic acid (see US20120245177A1)
(1) Adding 5L of purified water and 1kg of calcium levofolinate into a 10L glass reaction kettle, uniformly mixing, heating to 40 ℃, adding 0.25kg of sodium carbonate, adjusting the pH value to 8.0 by using acetic acid, filtering, removing calcium carbonate to obtain a sodium levofolinate solution, adding 8.5L of purified water and 0.51L of isopropanol, and diluting for later use;
(2) adding 3.5L of purified water and 0.35L of isopropanol into a 20L glass reaction kettle, uniformly stirring, heating to 45 ℃, slowly adding the sodium levofolinate solution obtained in the step (1) and 0.5L of 25% hydrochloric acid prepared in advance, monitoring the change of the pH value of the solution in the reaction kettle by using a pH meter, controlling the adding speed of the hydrochloric acid to maintain the pH value of the solution between 3.5 and 4.5 when the hydrochloric acid is added, controlling the adding speed of the sodium levofolinate solution when the sodium levofolinate solution is added to slowly reduce the temperature of the solution in the reaction kettle to 35 ℃, after the sodium levofolinate solution is completely added, adjusting the pH value of the solution to 4.0, controlling the temperature to 35 ℃ to separate out crystals of the levofolinate, filtering, washing the obtained solid water, and performing vacuum drying to obtain 0.55kg of the levofolinate crystals, wherein the yield is as follows: 70% (purity 96.85%, residue on ignition: 0.8%, XRD shown in figure 6).
The levofolinic acid crystal samples obtained in the examples and comparative examples were sealed and encapsulated in a low density polyethylene bag and then sealed and encapsulated in a composite aluminum film bag, and stability tests were performed in the dark at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 65%. + -. 5%, and the specific results are shown in Table 2 below.
TABLE 2 stability data for levofolinic acid crystal samples
The structural formulae of impurity 10, impurity 6 and impurity 4 are shown in table 3.
TABLE 3 different impurity Structure
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (15)
1. A preparation method of levofolinic acid crystals is characterized by comprising the following steps:
(1) adding amorphous levofolinic acid into an alcohol-water mixed solvent, and uniformly stirring and dispersing at 0-30 ℃ to obtain a levofolinic acid dispersion; the alcohol-water mixed solvent is a mixed solvent of methanol and/or ethanol and water, wherein the volume ratio of the methanol and/or ethanol to the water in the alcohol-water mixed solvent is 1: 3-5;
(2) adding alkali liquor into the levofolinic acid dispersion obtained in the step (1), adjusting the pH value of the levofolinic acid dispersion to 4.1-4.2, stirring and carrying out crystal transformation at the temperature of-20-35 ℃, separating out solids after crystal transformation, washing and drying to obtain levofolinic acid crystals; the alkali liquor is prepared from one or more of hydroxides, acetates or carbonates of alkaline earth metals and a mixed solution of water and methanol or ethanol.
2. The method for producing crystalline levofolinic acid according to claim 1, wherein in step (2), the crystalline levofolinic acid has an XRD pattern as shown in figure 1.
3. The method for preparing crystalline levofolinic acid as claimed in claim 1, wherein in the step (1), the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 3-100 kg/L.
4. The method for preparing crystalline levofolinic acid according to claim 3, wherein in the step (1), the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 4-50 kg/L.
5. The method for preparing crystalline levofolinic acid according to claim 3, wherein in the step (1), the mass-to-volume ratio of the amorphous levofolinic acid to the alcohol-water mixed solvent is 1: 4.5-10 kg/L.
6. The method for producing crystalline levofolinic acid as claimed in claim 1, wherein the temperature for stirring and dispersing in step (1) is 0-15 ℃.
7. The method for preparing crystals of levofolinic acid as claimed in claim 6, wherein the temperature for stirring and dispersing in step (1) is 0-5 ℃ or 5-10 ℃.
8. The method for preparing crystals of levofolinic acid as claimed in claim 1, wherein in step (2), the concentration of the alkali solution is 1-50%.
9. The method for preparing crystals of levofolinic acid as claimed in claim 8, wherein in step (2), the concentration of the alkali solution is 5-15%.
10. The method for preparing crystals of levofolinic acid as claimed in claim 8 or 9, wherein in step (2), the alkali solution is prepared from one or more of sodium hydroxide, sodium acetate or sodium carbonate, and a mixed solution of water and methanol or ethanol.
11. The method for preparing crystals of levofolinic acid as claimed in claim 10, wherein in step (2), the alkali solution is prepared from a mixed solution of sodium hydroxide, water and methanol or ethanol, and the volume ratio of methanol or ethanol to water in the alkali solution is 1: 1-6.
12. The method for preparing crystals of levofolinic acid as claimed in claim 11, wherein in step (2), the alkali solution is prepared from a mixed solution of sodium hydroxide, water and methanol or ethanol, and the volume ratio of methanol or ethanol to water in the alkali solution is 1: 3-5.
13. The method for preparing levofolinic acid crystal according to claim 1, wherein in the step (2), the temperature for stirring and crystal transformation is 0-20 ℃; when stirring and crystal transformation are carried out, paddle stirring is selected, and the stirring and crystal transformation time is 4-16 hours.
14. The method for preparing levofolinic acid crystal according to claim 13, wherein in the step (2), the temperature for stirring and crystal transformation is 5-10 ℃; when stirring and crystal transformation are carried out, paddle stirring is selected, and the stirring and crystal transformation time is 8-12 hours.
15. The method for preparing crystalline levofolinic acid as claimed in claim 1, wherein in the step (2), the solvent selected during washing is one or more of water, methanol or ethanol; during drying, the drying mode is decompression freeze-drying, vacuum drying or blast drying, and the drying temperature is-20-30 ℃.
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