CN102702200B - (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof - Google Patents
(6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof Download PDFInfo
- Publication number
- CN102702200B CN102702200B CN201210125133.2A CN201210125133A CN102702200B CN 102702200 B CN102702200 B CN 102702200B CN 201210125133 A CN201210125133 A CN 201210125133A CN 102702200 B CN102702200 B CN 102702200B
- Authority
- CN
- China
- Prior art keywords
- calcium salt
- methyltetrahydrofolate
- crystal formation
- salt crystal
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and a preparation process thereof. Diffraction peaks are generated in an X-ray diffraction pattern of the (6RS)-5-methyl tetrahydrofolate calcium salt crystal form when the 2theta angle is equal to 9.2+/-0.2, 15.0+/-0.2, 15.6+/-0.2, 21.1+/-0.2, 23.3+/-0.2, 27.2+/-0.2 and 28.6+/-0.2. The (6RS)-5-methyl tetrahydrofolate calcium salt crystal form has the advantages of high stability, purity and reproducibility, higher adaptability to industrial preparation in scale, and the like.
Description
Technical field
The invention belongs to drug crystal forms field, be specifically related to (6RS)-5-methyltetrahydrofolate calcium salt crystal formation and its production and use.
Background technology
5-methyltetrahydrofolate (English popular name: 5-methyltetrahydrofolate, be called for short 5-MTHF), chemical name is N-[4-[[(2-amino-1,4,5,6,7,8-six hydrogen-4-oxygen-5-methyl-6-pteridine radicals) methyl] amino] benzoyl]-Pidolidone, structural formula is suc as formula shown in I:
Formula I
The 5-methyltetrahydrofolate of chemosynthesis be mainly by folic acid through hydrogenation and the acquisition that methylates, conventionally in the time of 5,6 double-bond hydrogenations, form optical activity carbon atoms at 6, exist with the form of 6R-or 6S-5-methyl tetrahydrofolate.5-methyltetrahydrofolate is being usually to exist with the form of salt on the market, especially alkaline earth salt, particularly calcium salt.In prior art, take many methods to prepare the crystal formation of 5-methyltetrahydrofolate and salt thereof.
US6441168 discloses by pyroprocessing, and crystallization in the aqueous solution has obtained the crystal formation of four kinds of stable 5-methyltetrahydrofolate calcium salts, is respectively I, II, III, IV.
WO2008144953 discloses a kind of method of preparing amorphous 5-methyltetrahydrofolate calcium salt, by the slowly crystallization acquisition at low temperatures of 5-methyltetrahydrofolate calcium saline solution.
US5006655 disclose a kind of with 5,10-methyne (6RS)-tetrahydrofolic acid (THFA) for raw material, fractional crystallization in polar solvent, separates diastereomer, then reduces, salify obtains the method for 5-methyltetrahydrofolate salt.
The method of what the past was known prepare 5-methyltetrahydrofolate calcium salt crystal formation all obtains by conventional crystallization means in aqueous medium.
Summary of the invention
An object of the present invention is to provide one (6RS)-5-methyltetrahydrofolate calcium salt crystal formation.
The preparation method of another object of the present invention is to provide above-mentioned (6RS)-5-methyltetrahydrofolate calcium salt crystal formation.
The 3rd object of the present invention is to provide the pharmaceutical composition of above-mentioned (6RS)-5-methyltetrahydrofolate calcium salt crystal formation.
The 4th object of the present invention is to provide the purposes of above-mentioned (6RS)-5-methyltetrahydrofolate calcium salt crystal formation.
Object of the present invention can reach by following measures:
One aspect of the present invention provides a kind of (6RS)-5-methyltetrahydrofolate calcium salt crystal formation, use Cu-Ka radiation, its x-ray diffraction pattern, has diffraction peak to spend the 2 θ angles that represent at 9.2 ± 0.2,15.0 ± 0.2,15.6 ± 0.2,21.1 ± 0.2,23.3 ± 0.2,27.2 ± 0.2 and 28.6 ± 0.2 places.Further (6RS)-5-methyltetrahydrofolate calcium salt x-ray diffraction pattern is substantially as Fig. 1.
Another aspect of the present invention also provides one to prepare the method for (6RS)-5-methyltetrahydrofolate calcium salt, and the method comprises the steps:
(1) (6RS)-5-methyltetrahydrofolate is first neutralized to entirely molten with alkali in aqueous medium;
(2) be heated to 40 DEG C～100 DEG C;
(3) add calcium salt or calcium salt soln;
(4) ultrasonic crystallization, isolates crystal.
Ultrasonic is a kind of simple, cheap technology, uses safety, convenient.Ultrasonic wave can be strengthened nucleation and the growth of crystal on the one hand.In crystallisation process, introduce ultrasonic wave and can cause cavitation phenomenon, in the time that breaking, cavitation bubble can produce certain microjet, microjet smashes the crystal grain with certain size, and crystal after fragmentation has the crystal seed of part as crystal growth, thereby has promoted the growth of crystal; Ultrasonic wave is equivalent to catalyzer on the other hand in crystallisation process, excites molecular motion by translation, rotation, upset, thereby accelerates the crystallization rate of whole system, shortens crystallization time.Ultrasonic wave can also be improved the size-grade distribution of crystal product, and along with the increase of ultrasonic power, crystal grain presents the trend reducing.Do not introduce pollutent owing to not needing to add in other reagent and crystallisation process, therefore ultrasonic wave can be prepared very pure crystalline substance, and this is very important for some to the very strict material of purity requirement, particularly pharmaceutical prod and food.Stimulate graining method to compare with the graining method of charging seed with other, the desired degree of supersaturation of ultrasonic crystallization is lower, fast growth, and the crystal of gained is more even, complete, bright and clean, and crystal size distribution scope is less, and the variation coefficient is lower.
Ultrasonic wave starts to be applied to crystallization field from nineteen twenty-seven, in recent years, has obtained further promotion in pharmacy and Fine Chemical.The people such as Ishtiaq comment the application (World Applied Sciences Journal (2009), 6 (7), 886-893) of ultrasonic wave at pharmacy field.But up to now, in whole pharmaceutical industry, only have fragmentary several sections of papers and patent openly and this technology of using ultrasound ripple crystallization, as (Organic Process Research & Development 2005 such as paroxetine, aspartame, hexanodioic acid, Partusisten Hydrogen bromides, 9,923-932).
Contriver first by ultrasonic applications in the crystallization field of 5-methyltetrahydrofolate and salt thereof.We find in experiment: be 20～100KHz in ultrasonic frequency, when power is 50～2000w, gained crystal is more even, complete, bright and clean, and purity is higher, reaches more than 99.0%; Preferably ultrasonic frequency is 40～80KHz, and power is 100～1000w.
Aqueous medium described in step (1) is the solution of the aqueous solution of water, salt or water and the organic solvent composition that can mix with water, can be also salt; Organic solvent comprises C1-C4 alcohols, as methyl alcohol, and ethanol, n-propyl alcohol, Virahol, propyl carbinol; Ester class, as ethyl acetate, ritalin, propyl acetate, N-BUTYL ACETATE; Dimethyl formamide, dimethyl sulfoxide (DMSO) and methyl-2-pyrrolidone.Preferred aqueous medium is water.
Alkali described in step (1) be can with the inorganic or organic bases of (6RS)-5-methyltetrahydrofolate salify, be selected from alkali, carbonate, supercarbonate, ammoniacal liquor, amine, pyridines or the piperazines of basic metal or alkaline-earth metal, preferably: potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, ammoniacal liquor, Monomethylamine, 4-lutidine or piperazine;
Neutralizing and referring generally to neutralization to pH value 7.0 left and right with alkali in step (1), is generally pH value 6.5～7.5, is preferably neutralized to pH value 7.0～7.5, is most preferably neutralized to pH value 7.0.Alkali can directly add, and form (as the aqueous solution) that also can solution adds.Present method there is no specific requirement to the consumption of aqueous medium, is advisable with general reaction or crystallization medium consumption.
Heating temperature is preferably 40 DEG C-90 DEG C in step (2), and further preferably 50 DEG C-90 DEG C, more preferably 60 DEG C-80 DEG C.
In step (3), calcium salt refers to inorganic salt or the organic salt of the calcium ion that dissolves in or be partially soluble in aqueous medium, for example calcium chloride, calcium chloride hexahydrate; While adopting calcium salt soln, generally adopt the calcium saline solution of 5wt%～30wt%.
In step (4) ultrasonic crystallization and isolate crystal after generally also wash and be dried the step of (as vacuum drying at 20 DEG C～40 DEG C).
Ultrasonic wave preparation (6RS)-5-methyltetrahydrofolate calcium salt crystal formation can naturally carry out or introduce corresponding (6RS)-5-methyltetrahydrofolate calcium salt crystal seed and carry out.
Present method can obtain above-mentioned (the 6RS)-5-methyltetrahydrofolate calcium salt crystal formation of chemical purity more than 99.0%, and its moisture is generally 13%～16%, is further 14%～15%.
The medicinal compositions that the present invention also provides one to comprise above-mentioned (6RS)-5-methyltetrahydrofolate calcium salt crystal formation, it also can contain pharmaceutically acceptable auxiliary material or carrier.Described carrier comprises thinner, tackiness agent, disintegrating agent, lubricant etc., and these auxiliary materials are existing conventional auxiliary material.The dosage form of composition is oral solid formulation or injection, as tablet, capsule, orally disintegrating tablet, lozenge, sustained-release preparation, injection, lyophilized powder etc., adopts the method for corresponding formulation prepare and get final product.
A kind of preparation, includes (6RS)-5-methyltetrahydrofolate calcium salt crystal formation of the present invention of effective dose.
The present invention further also provides (6RS)-5-methyltetrahydrofolate calcium salt crystal formation in the purposes of preparing in medicine.
The example that (6RS)-5-methyltetrahydrofolate calcium salt crystal formation of the present invention can be used for treating disease and symptom includes but not limited to: as the toxinicide of antifol (as methotrexate, Pyrimethamine hcl or trimethoprim etc.); Be used for preventing caused serious toxicity effect after the excessive or heavy dose for the treatment of of methotrexate; By the caused megaloblastic anemia of folic acid deficiency; During with Fluracil combined utilization, be used for the treatment of Advanced Colon Cancer, the rectum cancer; With progestogen and or oestrogenic hormon combine the used time, can be used as contraceptive bian, also can be used for reducing the risk of neural tube defect, particularly ventricle valve defect, the risk of reduction Urinary malformation, harelip, cleft palate, spontaneous abortion; Treatment endometriosis; Treatment mental disease, particularly dysthymia disorders; Be used for prevention and Cardiovarscular with acetylsalicylic acid coupling; Wait coupling to be used for the treatment of essential hypertension with toxilic acid Yi Na Puli; Be used for the treatment of the autoimmune disorders such as the fresh and rheumatoid arthritis of ox-hide; For promote some antiparasitic-as Trimethoprim BP-sulfamethoxazole-consistency and for reducing the two denitrifications of chemotherapy assorted-toxicity of tetrahydrofolic acid (THFA)s etc.
(6RS)-5-methyltetrahydrofolate calcium salt crystal formation of the present invention has that good stability, purity are high, favorable reproducibility, be more suitable for industrially scalable and the advantage such as prepare, and is conducive to production and the storage of pharmaceutical preparation.Method of the present invention is utilized ultrasonic response in salification process, can obtain stable, purity is high, favorable reproducibility, evengranular 5-methyltetrahydrofolate calcium salt crystal formation, for the preparation of 5-methyltetrahydrofolate calcium salt crystal formation opens up a new way.
Brief description of the drawings
Fig. 1 is the X-ray diffracting spectrum of (6RS)-5-methyltetrahydrofolate calcium salt crystal formation of the present invention.
Embodiment
Embodiment is that method of the present invention describes in detail for example below, but the scope not limiting the present invention in any way.
Embodiment 1
500 ml deionized water are placed in container, add 50 grams of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.5 with 2mol/L sodium hydroxide entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 40KHz, power be 500w, be heated to 70 DEG C, the calcium chloride solution (20 grams of chloride containing calcium) that adds 10wt%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 27.1 grams of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.2% (HPLC detection), content 100.2%, moisture 15.0%.
Embodiment 2
400 ml deionized water are placed in container, add 30 grams of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.0 with 2mol/L sodium hydroxide entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 60KHz, power be 100w, be heated to 53 DEG C, the calcium chloride solution (15 grams of chloride containing calcium) that adds 10wt%, ultrasonic reaction filtered after 0.5 hour, washing.25 DEG C of vacuum dryings, obtain 20.0 grams of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.1% (HPLC detection), content 101.1%, moisture 14.8%.
Embodiment 3
600 ml deionized water are placed in container, add 50 grams of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.2 with 2mol/L sodium hydroxide entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 40KHz, power be 800w, be heated to 40 DEG C, the calcium chloride solution (20 grams of chloride containing calcium) that adds 10wt%, ultrasonic reaction filtered after 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 28.2 grams of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.2% (HPLC detection), content 101.0%, moisture 14.5%.
Embodiment 4
1000 milliliters of deionized waters, add 80 grams of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.2 with 2mol/L sodium bicarbonate entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 80KHz, power be 1000w, be heated to 58 DEG C, add the calcium chloride solution (30 grams of chloride containing calcium) of 10wt%, ultrasonic reaction filters for 0.5 hour, washing.30 DEG C of vacuum dryings, obtain 43.5 grams of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.2% (HPLC detection), content 100.0%, moisture 14.7%.
Embodiment 5
1200 ml deionized water are put into container, add 50 grams of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.0 with 2mol/L sodium hydroxide entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 60KHz, power be 1000w, be heated to 70 DEG C, add the calcium chloride solution (25 grams of chloride containing calcium) of 20wt%, ultrasonic reaction filters for 40 minutes, washing.30 DEG C of vacuum dryings, obtain 28.0 grams of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.5% (HPLC detection), content 100.6%, moisture 14.0%.
Embodiment 6
100 liters of deionized waters are put into container, add 10 kilograms of (6R, S)-5-MTHF, stir that lower to neutralize pH value 7.0 with 2mol/L sodium hydroxide entirely molten to (6R, S)-5-MTHF, in the ultrasound reactor that to transfer to frequency and be 80KHz, power be 5000w, be heated to 60 DEG C, add the calcium chloride solution (3.0 kilograms of chloride containing calcium) of 10wt%, ultrasonic reaction filters for 1.0 hours, washing.30 DEG C of vacuum dryings, obtain 5.8 kilograms of white crystals of the present invention (6R, S)-5-MTHF calcium salt.Chemical purity 99.0% (HPLC detection), content 100.8%, moisture 14.2%.
Embodiment 7, study on the stability
Leaving (6RS)-5-methyltetrahydrofolate calcium salt crystal formation in temperature is in 25 DEG C and the relative humidity air that is 60%, the content of periodic measurement residue (6RS)-5-methyltetrahydrofolate calcium salt crystal formation:
| Storage number of days | Outward appearance | (6RS) content of-5-MTHF |
| 0 | White crystals | 100.00％ |
| 15 | White crystals | 99.82％ |
| 30 | White crystals | 99.34％ |
| 45 | White crystals | 98.90％ |
| 60 | White crystals | 98.20％ |
Above result shows, (6RS)-5-methyltetrahydrofolate calcium salt stable crystal form is good, is conducive to production and the storage of pharmaceutical preparation.
(6RS)-5-methyltetrahydrofolate calcium salt crystal formation of the present invention
Instrument model: Bruker D8 advance XRD
Diffracted ray: CuK α (40kV, 40mA)
Scanning speed: 8 °/min (2 θ value)
Sweep limit: 2 °～45 ° (2 θ value)
Peak Search Report(42Peaks，Max P/N＝18.8)
PEAK：27-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 | 5.621 | 15.7107 | 478 | 73 | 3.9 | 1668 | 3.4 | 0.388 |
| 2 | 6.239 | 14.1542 | 453 | 138 | 7.4 | 1116 | 2.3 | 0.137 |
| 3 | 8.320 | 10.6180 | 588 | 201 | 10.8 | 1922 | 4.0 | 0.163 |
| 4 | 9.241 | 9.5626 | 577 | 1858 | 100.0 | 48529 | 100.0 | 0.444 |
| 5 | 9.719 | 9.0926 | 557 | 543 | 29.2 | 12849 | 26.5 | 0.402 |
| 6 | 11.461 | 7.7146 | 506 | 235 | 12.6 | 6949 | 14.3 | 0.503 |
| 7 | 12.280 | 7.2016 | 512 | 401 | 21.6 | 7780 | 16.0 | 0.330 |
| 8 | 12.681 | 6.9748 | 501 | 128 | 6.9 | 2041 | 4.2 | 0.271 |
| 9 | 13.560 | 6.5247 | 493 | 320 | 17.2 | 5761 | 11.9 | 0.306 |
| 10 | 14.679 | 6.0296 | 672 | 343 | 18.5 | 5182 | 10.7 | 0.257 |
| 11 | 15.040 | 5.8858 | 566 | 618 | 33j | 16693 | 34.4 | 0.459 |
| 12 | 15.560 | 5.6902 | 737 | 1391 | 74.9 | 20753 | 42.8 | 0.254 |
| 13 | 17.060 | 5.1931 | 511 | 234 | 12.6 | 5061 | 10.4 | 0.368 |
| 14 | 17.529 | 5.0552 | 524 | 84 | 4.5 | 596 | 1.2 | 0.121 |
| 15 | 18.461 | 4.8021 | 556 | 294 | 15.8 | 7138 | 14.7 | 0.413 |
| 16 | 18.819 | 4.7116 | 569 | 286 | 15.4 | 7339 | 15.1 | 0.436 |
| 17 | 19.780 | 4.4847 | 579 | 389 | 20.9 | 8625 | 17.8 | 0.377 |
| 18 | 20.400 | 4.3497 | 639 | 279 | 15.0 | 2948 | 6.1 | 0.180 |
| 19 | 21.139 | 4.1993 | 557 | 1232 | 66.3 | 21783 | 44.9 | 0.301 |
| 20 | 22.341 | 3.9760 | 594 | 437 | 23.5 | 5084 | 10.5 | 0.198 |
| 21 | 22.799 | 3.8973 | 662 | 83 | 4.5 | 481 | 1.0 | 0.099 |
| 22 | 23.261 | 3.8209 | 647 | 465 | 25.0 | 12080 | 24.9 | 0.442 |
| 23 | 23.941 | 3.7138 | 660 | 297 | 16.0 | 7968 | 16.4 | 0.456 |
| 24 | 24.798 | 3.5874 | 664 | 312 | 16.8 | 5748 | 11.8 | 0.313 |
| 25 | 25.340 | 3.5119 | 613 | 821 | 44.2 | 14735 | 30.4 | 0.305 |
| 26 | 26.616 | 3.3463 | 725 | 152 | 8.2 | 1980 | 4.1 | 0.221 |
| 27 | 27.238 | 3.2713 | 648 | 417 | 22.4 | 17013 | 35.1 | 0.694 |
| 28 | 27.579 | 3.2316 | 700 | 576 | 31.0 | 7985 | 16.5 | 0.236 |
| 29 | 28.560 | 3.1228 | 589 | 483 | 26.0 | 6660 | 13.7 | 0.234 |
| 30 | 29.619 | 3.0136 | 548 | 339 | 18.2 | 8607 | 17.7 | 0.432 |
| 31 | 31.800 | 2.8116 | 441 | 89 | 4.8 | 1721 | 3.5 | 0.329 |
| 32 | 32.861 | 2.7233 | 457 | 105 | 5.7 | 1534 | 3.2 | 0.248 |
| 33 | 34.184 | 2.6208 | 464 | 82 | 4.4 | 3956 | 8.2 | 0.820 |
| 34 | 34.798 | 2.5760 | 470 | 78 | 4.2 | 2569 | 5.3 | 0.560 |
| 35 | 35.147 | 2.5512 | 457 | 78 | 4.2 | 1349 | 2.8 | 0.294 |
| 36 | 36.145 | 2.4830 | 426 | 98 | 5.3 | 599 | 1.2 | 0.104 |
| 37 | 36.582 | 2.4543 | 437 | 74 | 4.0 | 331 | 0.7 | 0.076 |
| 38 | 37.700 | 2.3841 | 443 | 205 | 11.0 | 4485 | 9.2 | 0.372 |
| 39 | 38.402 | 2.3421 | 429 | 104 | 5.6 | 1652 | 3.4 | 0.270 |
| 40 | 39.322 | 2.2894 | 410 | 113 | 6.1 | 2065 | 4.3 | 0.311 |
| 41 | 40.499 | 2.2255 | 399 | 134 | 7.2 | 4627 | 9.5 | 0.587 |
| 42 | 41.444 | 2.1769 | 389 | 115 | 6.2 | 3807 | 7.8 | 0.563 |
Claims (8)
1. (6RS)-5-methyltetrahydrofolate calcium salt crystal formation, is characterized in that its X-ray diffracting spectrum is that 9.2 ± 0.2,15.0 ± 0.2,15.6 ± 0.2,21.1 ± 0.2,23.3 ± 0.2,27.2 ± 0.2 and 28.6 ± 0.2 places have diffraction peak at 2 θ angles; Its X-ray diffracting spectrum is substantially as Fig. 1.
2. a preparation method for crystal formation described in claim 1, is characterized in that:
A) (6RS)-5-methyltetrahydrofolate is first neutralized to entirely molten with alkali in aqueous medium;
Described aqueous medium is the solution of water or water and the organic solvent composition that can mix with water; Described alkali be can with the inorganic or organic bases of (6RS)-5-methyltetrahydrofolate salify, be selected from alkali, carbonate, supercarbonate, ammoniacal liquor, amine, pyridines or the piperazines of basic metal or alkaline-earth metal;
B) be heated to 40 DEG C～100 DEG C;
C) add calcium salt or calcium salt soln;
D) ultrasonic crystallization, isolates crystal formation; Wherein hyperacoustic frequency is 20～100 KHz, and hyperacoustic power is 50～10000w.
3. method according to claim 2, is characterized in that alkali described in step a) is potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, ammoniacal liquor, Monomethylamine, 4-lutidine or piperazine; Calcium salt described in step c) is calcium chloride or calcium chloride hexahydrate.
4. method according to claim 2, is characterized in that the Heating temperature in step b) is 60-80 DEG C.
5. method according to claim 2, is characterized in that in step d), hyperacoustic frequency is 40～80 KHz, and ultrasonic power is 100～5000w.
6. a pharmaceutical composition, is characterized in that said composition comprises (6RS)-5-methyltetrahydrofolate calcium salt crystal formation claimed in claim 1 as its activeconstituents and pharmaceutically acceptable auxiliary material.
7. a preparation, includes (6RS)-5-methyltetrahydrofolate calcium salt crystal formation claimed in claim 1 of effective dose.
(6RS)-5-methyltetrahydrofolate calcium salt crystal formation claimed in claim 1 in preparation as the purposes aspect medicine or the foodstuff additive of active constituents of medicine.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210125133.2A CN102702200B (en) | 2012-04-25 | 2012-04-25 | (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof |
| BR112014017939-5A BR112014017939A2 (en) | 2012-01-20 | 2012-12-17 | SALT CRYSTAL FORM OF (6S)-5-METHYL-TETRA-HYDROFOLATE AND METHOD FOR PREPARATION OF THE SAME |
| US14/373,262 US9150982B2 (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6S)-5-methyltetrahydrofolate salt and method for preparing same |
| CA2861891A CA2861891C (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| PL12865798T PL2805952T3 (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| IN6942DEN2014 IN2014DN06942A (en) | 2012-01-20 | 2012-12-17 | |
| EP12865798.8A EP2805952B1 (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| PCT/CN2012/086794 WO2013107236A1 (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| ES12865798T ES2715599T3 (en) | 2012-01-20 | 2012-12-17 | Salt crystal form of (6S) -5-methyltetrahydrofolate and method to prepare this |
| KR1020147023261A KR101694710B1 (en) | 2012-01-20 | 2012-12-17 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| JP2014552484A JP6166736B2 (en) | 2012-01-20 | 2012-12-17 | Crystalline form of (6S) -5-methyltetrahydrofolate and method for producing the same |
| HRP20190317TT HRP20190317T1 (en) | 2012-01-20 | 2019-02-18 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210125133.2A CN102702200B (en) | 2012-04-25 | 2012-04-25 | (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102702200A CN102702200A (en) | 2012-10-03 |
| CN102702200B true CN102702200B (en) | 2014-11-12 |
Family
ID=46895298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210125133.2A Active CN102702200B (en) | 2012-01-20 | 2012-04-25 | (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102702200B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013107236A1 (en) * | 2012-01-20 | 2013-07-25 | 连云港金康和信药业有限公司 | Crystal form of (6s)-5-methyltetrahydrofolate salt and method for preparing same |
| CN103214487A (en) * | 2013-04-12 | 2013-07-24 | 张家港威胜生物医药有限公司 | Synthesis of important medical chemical raw material (6S)-5-methyl tetrahydrofolate |
| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| EP3190112A4 (en) | 2014-09-04 | 2017-09-13 | Lianyungang Jinkang Hexin Pharmaceutical Co., Ltd. | Composition of (6s)-5-methyl tetrahydrofolic acid or salt thereof as well as preparation therefor and application thereof |
| 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 |
| CN113197902A (en) * | 2021-04-16 | 2021-08-03 | 连云港金康和信药业有限公司 | Application of 6S-5-methyltetrahydrofolic acid and pharmaceutically acceptable salt thereof in enhancing immunity |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH649550A5 (en) * | 1984-02-09 | 1985-05-31 | Eprova Ag | Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid |
| EP0539987A2 (en) * | 1991-10-29 | 1993-05-05 | Cerbios-Pharma S.A. | Process for the purification of crude alkalinic earth metal salts of N(5)-methyl-5,6,7,8-tetrahydrofolic acid |
| US5350850A (en) * | 1991-10-10 | 1994-09-27 | Apr Applied Pharma Research S.A. | Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N5 diastereoisomers in form of alkali and alkaline earth metal salts |
| CN1277197A (en) * | 1999-04-15 | 2000-12-20 | 阿泼洛发公司 | Stable crystal salt of 5-methyl tetrahydrofolic acid |
| CN101143863A (en) * | 2006-09-13 | 2008-03-19 | 南京莱因医药科技有限公司 | Resolution for 5-methyltetrahydrofolic acid and salifying method thereof |
-
2012
- 2012-04-25 CN CN201210125133.2A patent/CN102702200B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH649550A5 (en) * | 1984-02-09 | 1985-05-31 | Eprova Ag | Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid |
| US5350850A (en) * | 1991-10-10 | 1994-09-27 | Apr Applied Pharma Research S.A. | Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N5 diastereoisomers in form of alkali and alkaline earth metal salts |
| EP0539987A2 (en) * | 1991-10-29 | 1993-05-05 | Cerbios-Pharma S.A. | Process for the purification of crude alkalinic earth metal salts of N(5)-methyl-5,6,7,8-tetrahydrofolic acid |
| CN1277197A (en) * | 1999-04-15 | 2000-12-20 | 阿泼洛发公司 | Stable crystal salt of 5-methyl tetrahydrofolic acid |
| CN101143863A (en) * | 2006-09-13 | 2008-03-19 | 南京莱因医药科技有限公司 | Resolution for 5-methyltetrahydrofolic acid and salifying method thereof |
Non-Patent Citations (2)
| Title |
|---|
| A Convenient Method for the Preparation of dl-5-Methyltetrahydrofolic Acid (dl-5-methyl-5,6,7,8-tetrahydropteroyl-L-monoglutamic acid);J.A.BLAIR, et al.;《ANALYTICAL BIOCHEMISTRY》;19701231;第34卷;第376-381页 * |
| J.A.BLAIR et al..A Convenient Method for the Preparation of dl-5-Methyltetrahydrofolic Acid (dl-5-methyl-5 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102702200A (en) | 2012-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102702200B (en) | (6RS)-5-methyl tetrahydrofolate calcium salt crystal form and preparation process thereof | |
| EP2603509B1 (en) | Crystalline form of pyrimido[6,1-a] isoquinolin-4-one compound | |
| CN102584826B (en) | (6S)-5-methyl tetrahydrofolate crystal form and preparation method thereof | |
| CN102827153B (en) | Crystal formation of Azilsartan and preparation method thereof | |
| CN102382013A (en) | Preparation method of carbasalate calcium | |
| US9150982B2 (en) | Crystal form of (6S)-5-methyltetrahydrofolate salt and method for preparing same | |
| CN101490015A (en) | Rosuvastatin zinc salt | |
| CN107674056B (en) | Its application in treating hyperuricemia of Versulin derivative | |
| CN104557937B (en) | (6S) 5 methyl tetrahydrofolate salt crystal formations and preparation method thereof | |
| CN102775408B (en) | Stable 5-methyltetrahydrofolate crystal formation and preparation method thereof | |
| CN101597271A (en) | The derivative of Ailamode, its preparation method and medicinal application | |
| CZ2003140A3 (en) | Novel form of (R)-N-[5-methyl-8-(4-methylpiperazin-l-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide | |
| CN102775407B (en) | Stable unformed 5-methyltetrahydrofolate salt and preparation method thereof | |
| CN104530051B (en) | Stable (6R, S)-5-methyltetrahydrofolate crystal formation and preparation method thereof | |
| CN105237539A (en) | Crystal form A zinc (6S)-5-methyl tetrahydrofolate and preparation method therefor | |
| AU2022416318A1 (en) | Phenylethylidenehydrazine dimers and methods of using same | |
| CN107698591A (en) | (6S) -5-methyltetrahydrofolate zinc salt crystal formation and preparation method thereof | |
| CN101423540A (en) | Cytarabin 5 '-O-L-L-valine ester and pharmacy acceptable salt and preparation and application | |
| CN101528265A (en) | Inclusion complex of sibutramine and beta-cyclodextrin | |
| CN103242318A (en) | Salt of triazole-pyridazine derivative | |
| CN103509015A (en) | Salts of 14-hydroxyantofine derivative | |
| CN103664968A (en) | Salts of lycoris radiata lactone derivatives | |
| CN102875627A (en) | Stemona sessilifolia alkaloid salt and its pharmaceutical application | |
| CN103509014A (en) | Salts of antofine derivatives | |
| CN103288792A (en) | Salt of benzopyrone derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |