CN104557937A - (6S)-5-methyl tetrahydrofolate crystal form and preparation method thereof - Google Patents
(6S)-5-methyl tetrahydrofolate crystal form and preparation method thereof Download PDFInfo
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- CN104557937A CN104557937A CN201410280541.4A CN201410280541A CN104557937A CN 104557937 A CN104557937 A CN 104557937A CN 201410280541 A CN201410280541 A CN 201410280541A CN 104557937 A CN104557937 A CN 104557937A
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- methyltetrahydrofolate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention discloses a (6S)-5-methyl tetrahydrofolate crystal form and a preparation method thereof. The crystal form is a type C calcium (6S)-5-methyl tetrahydrofolate crystal form; the X-ray diffraction spectrum has diffraction peaks at angles 2 theta, namely 6.3+/-0.2 and 19.2+/-0.2. The type C calcium (6S)-5-methyl tetrahydrofolate crystal form has the advantages of excellent physicochemical properties, good stability, high purity, good reproducibility, better suitability for industrial large-scale preparation, and the like.
Description
Technical field
The invention belongs to drug crystal forms field, be specifically related to two kinds of (6S)-5-methyltetrahydrofolate salt crystal formations and its production and use.
Background technology
(6S)-5-methyltetrahydrofolate is the principal mode of tissue and blood folic acid, participates in multiple important biochemical reaction in body, the biosynthesis etc. of such as purine and thymus pyrimidine.It does not need through loaded down with trivial details enzymatic step in human body, can directly be utilized.In addition (6S)-5-methyltetrahydrofolate is the only medicine that can penetrate blood brain barrier in folic acid class medicine, have the effect of control Alzheimer (senile dementia), therefore it has the incomparable superiority of other folic acid class medicines.Be mainly used in active constituents of medicine and food additive, have prevention Foetus neural tube defect, arteriosclerosis, the effects such as treatment megaloblastic anemia.
(6S) chemical name of-5-methyltetrahydrofolate is (6S)-N-[4-[[(2-amino-Isosorbide-5-Nitrae, 5,6,7,8-six hydrogen-4-oxygen-5-methyl-6-pteridine radicals) methyl] amino] benzoyl]-Pidolidone, be called for short (6S)-5-MTHF.Structural formula is such as formula shown in I:
(6S)-5-methyltetrahydrofolate is being usually exist in a salt form on the market, especially alkali salt, particularly calcium salt.Many methods preparation (6S)-5-methyltetrahydrofolate and salt thereof has been taken in prior art.
US6441168 discloses by heat treatment, crystallization in polar solvent, obtains the crystal formation of four kinds of stable 5-methyltetrahydrofolate calcium salts, is respectively I, II, III, IV.
WO2008144953 discloses a kind of method preparing 5-methyltetrahydrofolate, obtains stable 5-methyltetrahydrofolate crystal formation and amorphous 5-methyltetrahydrofolate calcium salt simultaneously.
US5006655 discloses one with 5,10-methine (6RS)-tetrahydrofolic acid for raw material, fractional crystallization in polar solvent, and be separated diastereomer, then reduce, salify, obtains the method for 5-methyltetrahydrofolate salt.
CH699426 describes a kind of method through the unformed 5-methyltetrahydrofolate calcium salt of 13 step reaction preparation.
For medicinal compound, physical and chemical stability under its different storage condition is extremely important, but (6S)-5-methyltetrahydrofolate is very unstable, very easily degrade, particularly to oxygen and moisture extremely sensitive, be therefore difficult to obtain the product of enough purity for active constituents of medicine and food additive.
Summary of the invention
The object of the invention is to solve the deficiencies in the prior art, two kinds of i.e. stable, purity but also 5-methyltetrahydrofolate salt novel crystal forms that are high, favorable reproducibility are provided.
Another object of the present invention is to provide the preparation method of above-mentioned (6S)-5-methyltetrahydrofolate salt crystal formation newly.
3rd object of the present invention is to provide the pharmaceutical composition of above-mentioned (6S)-5-methyltetrahydrofolate salt crystal formation newly.
4th object of the present invention is to provide the purposes of above-mentioned (6S)-5-methyltetrahydrofolate salt crystal formation newly.
Object of the present invention can be reached by following measures:
A kind of (6S)-5-methyltetrahydrofolate salt crystal formation, this crystal formation is Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation or C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
One aspect of the present invention provides a kind of Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation, use Cu-Ka radiation, its x-ray diffraction pattern, there is diffraction maximum to spend the 2 θ angles represented at 3.2 ± 0.2 and 18.9 ± 0.2 places, particularly also have one or more diffraction maximum at 3.2 ± 0.2,6.4 ± 0.2,16.1 ± 0.2,16.8 ± 0.2,18.9 ± 0.2 and 20.0 ± 0.2 places.The X-ray diffracting spectrum of Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation presents strong diffraction maximum and low background spectra, indicates high-crystallinity.
The further x-ray diffraction pattern of Type B (6S)-5-methyltetrahydrofolate calcium salt is substantially as accompanying drawing 1.The chemical purity of Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation is further more than 99.0%.
The present invention provides a kind of C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation on the other hand, use Cu-Ka radiation, its x-ray diffraction pattern, there is diffraction maximum to spend 2 θ represented at 6.3 ± 0.2 and 19.2 ± 0.2 places, particularly also have one or more diffraction maximum at 3.2 ± 0.2,6.3 ± 0.2,13.2 ± 0.2,14.6 ± 0.2,19.2 ± 0.2 and 32.6 ± 0.2 places.The X-ray diffracting spectrum of C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation presents strong diffraction maximum and low background spectra, indicates high-crystallinity.
The further X-ray diffracting spectrum of C type (6S)-5-methyltetrahydrofolate calcium salt is substantially as accompanying drawing 2.The chemical purity of C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation is further more than 99.0%.
Moisture in Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation in the present invention or C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation is 12% ~ 17%, is 13.5% ~ 15.5% further.
Another aspect of the invention additionally provides a kind of method of preparation (6S)-5-methyltetrahydrofolate salt newly, and the method comprises the steps:
(1) (6S)-5-methyltetrahydrofolate elder generation is neutralized to entirely molten in an aqueous medium with alkali;
The solution that described aqueous medium is water, the aqueous solution of salt or water and the organic solvent that can mix with water form also can be salt; Preferred aqueous medium is water.Described alkali be can with the inorganic or organic base of (6S)-5-methyltetrahydrofolate salify, be selected from the alkali of alkali metal or alkaline-earth metal, carbonate, bicarbonate, ammonia, amine, pyridines or piperazines, preferably: potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, monomethyl amine, 4-lutidines or piperazine;
(2) be heated to more than 25 DEG C, be particularly heated to 25 DEG C ~ 100 DEG C;
(3) calcium salt or calcium salt soln is added;
Calcium salt refers to inorganic salt or the organic salt of the calcium ion dissolving in or be partially soluble in aqueous medium, such as calcium chloride, calcium chloride hexahydrate;
(4) ultrasonic crystallization, isolates crystal.
Ultrasound wave can make the solid solute of supersaturated solution produce rapid and mild precipitation, can strengthen crystal growth simultaneously.Owing to not needing to add other reagent and do not introduce pollutant in crystallization process, therefore, it is possible to the crystalline solid that preparation is very pure.We find in an experiment: be 20 ~ 100KHz in ultrasonic frequency, and power is 50 ~ 10000w, and gained crystal is more even, complete, bright and clean, and purity is higher, reaches more than 99.0%; Preferred ultrasonic frequency is 40 ~ 80KHz, and power is 100 ~ 4500w.
In step (2), the present inventor studies further and finds when heating-up temperature is when 25 DEG C ~ 45 DEG C interval, and the crystal obtained is B crystal form, preferential 38 DEG C ~ 45 DEG C.When temperature rises to more than 45 DEG C (as 45 DEG C ~ 100 DEG C), gained crystal is C crystal form, preferably adopts 65 DEG C ~ 70 DEG C.
Neutralizing with alkali in step (1) refers generally to neutralize pH value about 7.0, is generally pH value 6.5 ~ 7.5, is preferably neutralized to pH value 7.0 ~ 7.5, be most preferably neutralized to pH value 7.0.Alkali can directly add, and also can (as aqueous solution) add as a solution.The consumption of this method to aqueous medium there is no specific requirement, is advisable with general reaction or crystallization medium consumption.
When adopting calcium salt soln in step (3), generally adopt the calcium saline solution of 5% ~ 30%.
Ultrasonic crystallization in step (4) generally also carrying out after isolating crystal is washed and the step of dry (as vacuum drying at 20 DEG C ~ 40 DEG C).
Present invention also offers one and comprise above-mentioned Type B or/and the Pharmaceutical composition of C type (6S)-5-methyltetrahydrofolate calcium salt, it also can contain pharmaceutically acceptable adjuvant or carrier.Described carrier comprises diluent, binding agent, disintegrating agent, lubricant etc., and these adjuvants are existing customary adjuvant.The dosage form of compositions is oral solid formulation or injection, as tablet, capsule, oral cavity disintegration tablet, buccal tablet, sustained-release preparation, injection, lyophilized powder etc., adopts the method for corresponding dosage form prepare and get final product.
A kind of preparation, includes the Type B of effective dose or/and C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
Type B of the present invention or C type (6S)-5-methyltetrahydrofolate salt crystal formation can be applicable to prepare the medicine as active constituents of medicine or food additive aspect.The example that Type B of the present invention or C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation specifically can be used for disease therapy and symptom includes but not limited to: megaloblast folic acid deficiency anemia, prevention and therapy cardiovascular disease, prevention neurocele food deficiency disease, as the antidote (anti-folic acid relief agent) promoting antifol (especially aminopterin and the aminomethyl pterin) compatibility in treatment of cancer, for strengthening the curative effect of fluorinated pyrimidine, be used for the treatment of the autoimmune diseasees such as the fresh and rheumatoid arthritis of Corii Bovis seu Bubali, for promote some antiparasitic-as trimethoprim-sulfamethoxazole-the compatibility and to mix-the toxicity etc. of tetrahydrofolic acid for reducing denitrification two in chemotherapy.
The present inventor find Type B and C type (6S)-5-methyltetrahydrofolate calcium salt very stable, be 25 DEG C and relative humidity in temperature be deposit for a long time in the air of 60%, the color of crystal formation does not have significant change, and this is extremely important for being applied to by (6S)-5-methyltetrahydrofolate calcium salt pharmaceutical preparation.
The present inventor also finds that Type B and C type (6S)-5-methyltetrahydrofolate calcium salt have good rate of dissolution, in the water of 25 DEG C, just can reach capacity rapidly in 1 minute state, dissolution velocity not only can improve the preparing property of parenteral formulations as injection soon, facilitate suitability for industrialized production, oral formulations can also be made, oral administration for medicine has important biopharmaceutics advantage, because active medicine rate of dissolution behavior more rapidly can make active medicine be improved by the absorption rate of gastrointestinal wall.Crystal formation of the present invention also has that degree of crystallinity is high, even particle distribution, any surface finish, chemical purity reach 99.0% with first-class advantage in addition.
The method advantage of preparation of the present invention (6S)-5-methyltetrahydrofolate salt crystal formation is: reactions steps is simple, pollution-free, (the 6S)-5-methyltetrahydrofolate calcium salt novel crystal forms obtained has very high chemical stability, purity is high, dissolution velocity is fast, and bioavailability is high, provide new way for preparing novel (6S)-5-MTHF crystal salt.
Type B of the present invention and C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation have that physicochemical property excellence, good stability, purity are high, favorable reproducibility, be more suitable for industrially scalable and the advantage such as prepare.
Accompanying drawing explanation
Fig. 1 is the X-ray diffracting spectrum of Type B (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
Fig. 2 is the X-ray diffracting spectrum of C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
Fig. 3 is the rate of dissolution curve of Type B, C type and I type (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
Detailed description of the invention
Do not need to further describe, utilize previous explanation, those skilled in the art can implement the present invention to greatest extent.Preferred specific embodiments just illustratively, in no case limits content disclosed in this invention below.
Embodiment 1
40 ml deionized water are placed in a reservoir, add 3.0 grams of (6S)-5-MTHF, stirring lower 2mol/L liquid caustic soda, to neutralize pH value 7.5 entirely molten to (6S)-5-MTHF, transfer to that frequency is 40KHz, power is in the ultrasound reactor of 500w, be heated to 30 DEG C, add the calcium chloride solution (chloride containing calcium 1.0 grams) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 2.11 grams of white Type B (6S)-5-MTHF calcium salts.Chemical purity 99.7% (HPLC detection), content 101.5%, moisture 15.0%.
Embodiment 2
30 ml deionized water are placed in a reservoir, add 2.0 grams of (6S)-5-MTHF, stirring lower 2mol/L liquid caustic soda, to neutralize pH value 7.0 entirely molten to (6S)-5-MTHF, transfer to that frequency is 60KHz, power is in the ultrasound reactor of 100w, be heated to 43 DEG C, add the calcium chloride solution (chloride containing calcium 0.5 gram) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.25 DEG C of vacuum dryings, obtain 1.59 grams of white Type B (6S)-5-MTHF calcium salts.Chemical purity 99.5% (HPLC detection), content 100.1.1%, moisture 14.9%.
Embodiment 3
30 ml deionized water are placed in a reservoir, add 2.0 grams of (6S)-5-MTHF, stirring lower 2mol/L liquid caustic soda, to neutralize pH value 7.3 entirely molten to (6S)-5-MTHF, transfer to that frequency is 80KHz, power is in the ultrasound reactor of 1000w, be heated to 40 DEG C, add the calcium chloride solution (chloride containing calcium 1.2 grams) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 1.70 grams of white Type B (6S)-5-MTHF calcium salts.Chemical purity 99.2% (HPLC detection), content 99.4%, moisture 14.4%.
Embodiment 4
Deionized water 75 milliliters, add 3.0 grams of (6S)-5-MTHF, stirring lower 2mol/L sodium bicarbonate, to neutralize pH value 7.2 entirely molten to (6S)-5-MTHF, transfer to that frequency is 80KHz, power is in the ultrasound reactor of 4500w, be heated to 58 DEG C, add the calcium chloride solution (chloride containing calcium 1.8 grams) of 10%, ultrasonic reaction filters for 1.0 hours, washing.30 DEG C of vacuum dryings, obtain 2.60 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.0% (HPLC detection), content 101.1%, moisture 14.5%.
Embodiment 5
30 ml deionized water are placed in a reservoir, add 2.0 grams of (6S)-5-MTHF, stirring lower 2mol/L liquid caustic soda, to neutralize pH value 7.5 entirely molten to (6S)-5-MTHF, transfer to that frequency is 50KHz, power is in the ultrasound reactor of 1000w, be heated to 80 DEG C, add the calcium chloride solution (chloride containing calcium 0.5 gram) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 1.41 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.4% (HPLC detection), content 100.9%, moisture 13.8%.
Embodiment 6
450 ml deionized water are placed in a reservoir, add 30 grams of (6S)-5-MTHF, stirring lower 2mol/L sodium carbonate, to neutralize pH value 7.0 entirely molten to (6S)-5-MTHF, transfer to that frequency is 20KHz, power is in the ultrasound reactor of 500w, be heated to 65 DEG C, slowly add 10% calcium chloride solution (chloride containing calcium 7.0 grams), ultrasonic reaction filtered after 1.0 hours, washing.30 DEG C of vacuum dryings, obtain 16.2 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.6% (HPLC detection), content 101.2%, moisture 14.4%.
Embodiment 7
Deionized water 30 milliliters, add 2.0 grams of (6S)-5-MTHF, stirring lower 2mol/L liquid caustic soda, to neutralize pH value 7.5 to L-5-MTH F entirely molten, transfer to that frequency is 60KHz, power is in the ultrasound reactor of 350w, be heated to 70 DEG C, slowly add the calcium chloride solution (chloride containing calcium 0.5 gram) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 1.53 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.5% (HPLC detection), content 99.5%, moisture 14.6%.
Embodiment 8
Deionized water 50 milliliters, add 2.0 grams of (6S)-5-MTHF, it is entirely molten that stirring lower dropping 2mol/L liquid caustic soda neutralizes pH value 7.0 to L-5-MTHF, transfer to that frequency is 60KHz, power is in the ultrasound reactor of 500w, be heated to 90 DEG C, slowly add the calcium chloride solution (chloride containing calcium 1.2 grams) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 1.48 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.7% (HPLC detection), content 100.3%, moisture 14.5%.
Embodiment 9
Deionized water 50 milliliters, add 2.0 grams of (6S)-5-MTHF, it is entirely molten that stirring lower dropping 2mol/L liquid caustic soda neutralizes pH value 7.0 to L-5-MTH F, transfer to that frequency is 40KHz, power is in the ultrasound reactor of 1000w, be heated to 95 DEG C, slowly add the calcium chloride solution (chloride containing calcium 1.0 grams) of 10%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 1.56 grams of white C type (6S)-5-MTHF calcium salts.Chemical purity 99.4% (HPLC detection), content 101.0%, moisture 14.8%.
Embodiment 10 solubility test
Method: take (6S)-5-methyltetrahydrofolate calcium salt crystal formation in right amount in 100ml beaker, add the water of a certain amount of 25 DEG C, then be placed in the water-bath of temperature control 25 DEG C, ceaselessly stir, detect the dissolving situation of (6S)-5-methyltetrahydrofolate calcium salt crystal formation.
Disclosed in Type B, C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation and US6441168, the solubility results of I type crystal formation is listed in the table below:
| Crystal formation | Dissolubility (g/100ml) | Reach the time of steady statue |
| I type | 1.10 | 15min |
| Type B | 1.21 | 20s |
| C type | 1.32 | 10s |
Disclosed in Type B, C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation and US6441168, the rate of dissolution of I type crystal formation is shown in accompanying drawing 3.
Can find out from upper table and rate of dissolution figure, the dissolubility of (6S)-5-methyltetrahydrofolate calcium salt novel crystal forms in water that the present invention relates to slightly is better than the I type crystallization calcium salt of US6441168, and rate of dissolution is significantly better than I type crystallization calcium salt, more be conducive to absorbing of human body, thus there is better bioavailability.
Embodiment 11 study on the stability
In order to measure the stability of (6S)-5-MTHF calcium salt novel crystal forms, Type B to be left together with C type in temperature be 25 DEG C and relative humidity is in the air of 60%, the content of periodic measurement residue (6S)-5-MTHF calcium salt:
Above result shows, Type B and C type have good stability, is conducive to production and the reservoir of pharmaceutical preparation.
The X-ray diffracting spectrum condition of B crystal form and data
INSTRUMENT MODEL: Bruker D8advance XRD
Diffracted ray: CuK α (40kV, 40mA)
Sweep speed: 8 °/min (2 θ value)
Sweep limits: 2 ° ~ 45 ° (2 θ value)
Peak Search Report(23Peaks,Max P/N＝34.3)
PEAK:35-pts/Parabolic Filter,Threshold＝3.0,Cutoff＝0.1％,BG＝3/1.0,Peak-Top＝Summit
| # | 2-Theta | d(A) | BG | Height | I％ | Area | I％ | FWHM |
| 1 | 3.210 | 27.4991 | 358 | 5388 | 100.00 | 119300 | 100.00 | 0.398 |
| 2 | 6.428 | 13.7382 | 421 | 4248 | 78.84 | 72768 | 61.00 | 0.319 |
| 3 | 9.625 | 9.1814 | 417 | 889 | 16.50 | 9088 | 7.62 | 0.323 |
| 4 | 12.845 | 6.8861 | 620 | 835 | 15.50 | 2326 | 1.95 | 0.182 |
| 5 | 13.201 | 6.7012 | 701 | 1066 | 19.78 | 6650 | 5.57 | 0.306 |
| 6 | 13.651 | 6.4812 | 654 | 1113 | 20.66 | 7002 | 5.87 | 0.256 |
| 7 | 14.109 | 6.2720 | 739 | 1008 | 18.71 | 3306 | 2.77 | 0.206 |
| 8 | 14.695 | 6.0233 | 687 | 880 | 16.33 | 2014 | 1.69 | 0.175 |
| 9 | 15.331 | 5.7746 | 681 | 1013 | 18.80 | 4462 | 3.74 | 0.225 |
| 10 | 16.060 | 5.5141 | 768 | 1189 | 22.07 | 7970 | 6.68 | 0.318 |
| 11 | 16.813 | 5.2690 | 697 | 1205 | 22.36 | 16660 | 13.96 | 0.550 |
| 12 | 18.904 | 4.6904 | 821 | 1624 | 30.14 | 16232 | 13.61 | 0.339 |
| 13 | 20.046 | 4.4258 | 911 | 1461 | 27.12 | 11226 | 9.41 | 0.342 |
| 14 | 20.699 | 4.2875 | 807 | 1228 | 22.79 | 8607 | 7.21 | 0.343 |
| 15 | 22.539 | 3.9415 | 603 | 752 | 13.96 | 2269 | 1.90 | 0.256 |
| 16 | 23.405 | 3.7976 | 623 | 881 | 16.35 | 6140 | 5.15 | 0.399 |
| 17 | 23.956 | 3.7115 | 641 | 993 | 18.43 | 8761 | 7.34 | 0.418 |
| 18 | 24.983 | 3.5612 | 689 | 951 | 17.65 | 4687 | 3.93 | 0.300 |
| 19 | 25.869 | 3.4413 | 683 | 959 | 17.80 | 2372 | 1.99 | 0.144 |
| 20 | 27.448 | 3.2467 | 653 | 883 | 16.39 | 7498 | 6.28 | 0.547 |
| 21 | 28.339 | 3.1467 | 678 | 832 | 15.44 | 4059 | 3.40 | 0.442 |
| 22 | 30.984 | 2.8838 | 611 | 782 | 14.51 | 3233 | 2.71 | 0.317 |
| 23 | 32.523 | 2.7508 | 612 | 872 | 16.18 | 10971 | 9.20 | 0.708 |
The X-ray diffracting spectrum condition of C crystal form and data
INSTRUMENT MODEL: Bruker D8advance XRD
Diffracted ray: CuK α (40kV, 40mA)
Sweep speed: 8 °/min (2 θ value)
Sweep limits: 2 ° ~ 45 ° (2 θ value)
Peak Search Report(37Peaks,Max P/N＝46.1)
PEAK:35-pts/Parabolic Filter,Threshold＝3.0,Cutoff＝0.1％,BG＝3/1.0,Peak-Top＝Summit
| # | 2-Theta | d(A) | BG | Height | I％ | Area | I％ | FWHM |
| 1 | 3.151 | 28.0163 | 612 | 8740 | 89.06 | 165950 | 100.00 | 0.343 |
| 2 | 6.309 | 13.9974 | 689 | 9814 | 100.00 | 155754 | 93.86 | 0.286 |
| 3 | 9.447 | 9.3545 | 681 | 1601 | 16.31 | 16953 | 10.22 | 0.309 |
| 4 | 13.199 | 6.7022 | 913 | 4338 | 44.20 | 46545 | 28.05 | 0.228 |
| 5 | 13.612 | 6.4999 | 1029 | 2121 | 21.61 | 14775 | 8.90 | 0.227 |
| 6 | 14.166 | 6.2469 | 1072 | 1514 | 15.43 | 12344 | 7.44 | 0.441 |
| 7 | 14.639 | 6.0462 | 1057 | 4630 | 47.18 | 52370 | 31.56 | 0.246 |
| 8 | 15.329 | 5.7755 | 1055 | 1310 | 13.35 | 2233 | 1.35 | 0.147 |
| 9 | 16.001 | 5.5343 | 1133 | 2147 | 21.88 | 18187 | 10.96 | 0.301 |
| 10 | 16.534 | 5.3572 | 958 | 1409 | 14.36 | 15394 | 9.28 | 0.539 |
| 11 | 17.046 | 5.1973 | 1089 | 2406 | 24.52 | 14700 | 8.86 | 0.187 |
| 12 | 18.824 | 4.7103 | 1017 | 3484 | 35.50 | 74762 | 45.05 | 0.479 |
| 13 | 19.158 | 4.6288 | 1118 | 3998 | 40.74 | 84209 | 50.74 | 0.491 |
| 14 | 20.125 | 4.4085 | 1295 | 3176 | 32.36 | 30820 | 18.57 | 0.275 |
| 15 | 20.976 | 4.2316 | 1169 | 2397 | 24.42 | 22579 | 13.61 | 0.308 |
| 16 | 21.411 | 4.1466 | 1068 | 1503 | 15.31 | 5525 | 3.33 | 0.213 |
| 17 | 22.614 | 3.9287 | 863 | 1716 | 17.49 | 13799 | 8.32 | 0.271 |
| 18 | 24.073 | 3.6937 | 857 | 1619 | 16.50 | 9785 | 5.90 | 0.215 |
| 19 | 24.785 | 3.5892 | 884 | 1719 | 17.52 | 26584 | 16.02 | 0.503 |
| 20 | 25.022 | 3.5558 | 898 | 1971 | 20.08 | 26647 | 16.06 | 0.417 |
| 21 | 25.914 | 3.4354 | 884 | 1390 | 14.16 | 7075 | 4.26 | 0.235 |
| 22 | 26.858 | 3.3168 | 846 | 1262 | 12.86 | 10476 | 6.31 | 0.423 |
| 23 | 27.334 | 3.2601 | 852 | 1244 | 12.68 | 8923 | 5.38 | 0.359 |
| 24 | 27.674 | 3.2207 | 901 | 1048 | 10.68 | 1050 | 0.63 | 0.113 |
| 25 | 28.358 | 3.1446 | 915 | 1606 | 16.36 | 15814 | 9.53 | 0.384 |
| 26 | 28.908 | 3.0860 | 913 | 1339 | 13.64 | 16265 | 9.80 | 0.641 |
| 27 | 29.444 | 3.0310 | 977 | 1419 | 14.46 | 9424 | 5.68 | 0.358 |
| 28 | 30.251 | 2.9520 | 921 | 1248 | 12.72 | 3742 | 2.25 | 0.192 |
| 29 | 30.769 | 2.9035 | 880 | 1518 | 15.47 | 9728 | 5.86 | 0.256 |
| 30 | 31.537 | 2.8345 | 836 | 1196 | 12.19 | 4349 | 2.62 | 0.203 |
| 31 | 32.602 | 2.7443 | 813 | 1863 | 18.98 | 21721 | 13.09 | 0.347 |
| 32 | 35.722 | 2.5115 | 617 | 929 | 9.47 | 4980 | 3.00 | 0.268 |
| 33 | 37.675 | 2.3856 | 659 | 1229 | 12.52 | 10784 | 6.50 | 0.317 |
| 34 | 38.819 | 2.3179 | 633 | 884 | 9.01 | 5939 | 3.58 | 0.397 |
| 35 | 40.263 | 2.2381 | 607 | 776 | 7.91 | 4592 | 2.77 | 0.429 |
| 36 | 42.037 | 2.1476 | 580 | 988 | 10.07 | 14181 | 8.55 | 0.583 |
| 37 | 43.615 | 2.0735 | 563 | 841 | 8.57 | 6633 | 4.00 | 0.400 |
Claims (10)
1. (6S)-5-methyltetrahydrofolate salt crystal formation, is characterized in that this crystal formation is:
B () C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation, its X-ray diffracting spectrum is that 6.3 ± 0.2 and 19.2 ± 0.2 places have diffraction maximum at 2 θ angles.
2. (6S)-5-methyltetrahydrofolate salt crystal formation according to claim 1, is characterized in that this crystal formation is:
B () C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation, its X-ray diffracting spectrum is that 3.2 ± 0.2,6.3 ± 0.2,13.2 ± 0.2,14.6 ± 0.2,19.2 ± 0.2 and 32.6 ± 0.2 places have diffraction maximum at 2 θ angles.
3. (6S)-5-methyltetrahydrofolate salt crystal formation according to claim 2, is characterized in that:
B the X-ray diffracting spectrum of () described C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation is substantially as Fig. 2.
4. prepare a method for (6S)-5-methyltetrahydrofolate salt crystal formation, it is characterized in that:
A) (6S)-5-methyltetrahydrofolate elder generation is neutralized to entirely molten in an aqueous medium with alkali;
The solution that described aqueous medium is water, the aqueous solution of salt or water and the organic solvent that can mix with water form; Described alkali be can with the inorganic or organic base of (6S)-5-methyltetrahydrofolate salify, be selected from the alkali of alkali metal or alkaline-earth metal, carbonate, bicarbonate, ammonia, amine, pyridines or piperazines;
B) 45 DEG C ~ 100 DEG C are heated to;
C) calcium salt or calcium salt soln is added;
D) ultrasonic crystallization, isolates crystal formation.
5. method according to claim 4, is characterized in that alkali is potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, monomethyl amine, 4-lutidines or piperazine described in step a); Step b) described in calcium salt be calcium chloride or calcium chloride hexahydrate.
6. method according to claim 4, is characterized in that steps d) in hyperacoustic frequency be 20 ~ 100KHz, hyperacoustic power is 50 ~ 10000w.
7. method according to claim 6, is characterized in that steps d) in hyperacoustic frequency be 40 ~ 80KHz, ultrasonic power is 100 ~ 4500w.
8. a pharmaceutical composition, is characterized in that said composition comprises C type (6S)-5-methyltetrahydrofolate calcium salt crystal formation as its main active and pharmaceutically acceptable adjuvant.
9. a preparation, includes C type (the 6S)-5-methyltetrahydrofolate calcium salt crystal formation of effective dose.
10. (6S)-5-methyltetrahydrofolate salt crystal formation according to claim 1 in preparation as the purposes in the medicine of active constituents of medicine or food additive.
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| CN107698591A (en) * | 2015-09-25 | 2018-02-16 | 上海华理生物医药有限公司 | (6S) -5-methyltetrahydrofolate zinc salt crystal formation and preparation method thereof |
| CN110461845A (en) * | 2017-03-31 | 2019-11-15 | 默克专利股份有限公司 | 5- methyl-(6S)-tetrahydrofolic acid crystallization sodium salt |
| CN110461844A (en) * | 2017-03-31 | 2019-11-15 | 默克专利股份有限公司 | The crystallization binary sodium salt of 5- methyl-(6S)-tetrahydrofolic acid and organic base |
| CN110475778A (en) * | 2017-03-31 | 2019-11-19 | 默克专利股份有限公司 | 5- methyl-(6S)-tetrahydrofolic acid crystallization sodium salt |
| CN112368269A (en) * | 2018-07-06 | 2021-02-12 | 默克专利股份有限公司 | Crystalline salts comprising 5-methyl- (6S) -tetrahydrofolic acid and 4- (2-hydroxyethyl) -morpholine |
| CN112368050A (en) * | 2018-07-06 | 2021-02-12 | 默克专利股份有限公司 | Crystalline salts of 5-methyl- (6S) -tetrahydrofolic acid and ethyl L-valine |
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| CN107698591A (en) * | 2015-09-25 | 2018-02-16 | 上海华理生物医药有限公司 | (6S) -5-methyltetrahydrofolate zinc salt crystal formation and preparation method thereof |
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| CN110461844A (en) * | 2017-03-31 | 2019-11-15 | 默克专利股份有限公司 | The crystallization binary sodium salt of 5- methyl-(6S)-tetrahydrofolic acid and organic base |
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| CN110461844B (en) * | 2017-03-31 | 2024-03-12 | 默克专利股份有限公司 | Crystalline dibasic sodium salt of 5-methyl- (6S) -tetrahydrofolic acid and organic base |
| CN112368269A (en) * | 2018-07-06 | 2021-02-12 | 默克专利股份有限公司 | Crystalline salts comprising 5-methyl- (6S) -tetrahydrofolic acid and 4- (2-hydroxyethyl) -morpholine |
| CN112368050A (en) * | 2018-07-06 | 2021-02-12 | 默克专利股份有限公司 | Crystalline salts of 5-methyl- (6S) -tetrahydrofolic acid and ethyl L-valine |
| US11992491B2 (en) | 2018-07-06 | 2024-05-28 | Merck Patent Gmbh | Crystalline salts of 5-methyl-(6S)-tetrahydrofolic acid and L-valine ethyl ester |
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