CN104356038B - Eutectic of vitamin D2 and D3 and its production and use - Google Patents
Eutectic of vitamin D2 and D3 and its production and use Download PDFInfo
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- CN104356038B CN104356038B CN201410546268.5A CN201410546268A CN104356038B CN 104356038 B CN104356038 B CN 104356038B CN 201410546268 A CN201410546268 A CN 201410546268A CN 104356038 B CN104356038 B CN 104356038B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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Abstract
The present invention relates to a kind of vitamins D2And D3Eutectic, Preparation Method And The Use, and comprise the pharmaceutical composition of described eutectic. Described vitamins D2With D3The advantage that eutectic has degree of crystallinity height, water absorbability is little, and form regular crystal kenel, stability significantly strengthens, and is thus conducive to the art breading of medicine and the improvement of physical and chemical performance, it is to increase patent medicine performance.
Description
Technical field
The invention belongs to pharmaceutical chemistry and crystallization processes technical field, it is specifically related to vitamins D2With D3Eutectic and its production and use.
Background technology
Medicine cocrystallization (eutectic) refers to that the acid physiologically acceptable with other of active constituents of medicine (API) molecule, alkali, salt, non-ionic compound molecule are connected and be combined in same lattice with other non covalent bonds with hydrogen bond, pi-pi accumulation effect, Van der Waals force. The using value maximum in medicine of eutectic is exactly to introduce new component while not changing medicine covalent structure, greatly improve the physico-chemical property of medicine, such as stability, fusing point, dissolution rate, dissolution rate, bioavailability etc., and owing to the kind of part (CCF) has a lot, the character of medicine corresponding can also obtain adjustment in various degree. The difference of the physical properties that the solid form that each of active pharmaceutical ingredient is new shows can affect its stability in storage, compressibility and density and solubleness and dissolution rate.
Compared with other solid form such as salt, solvate, eutectic has bigger advantage in medicament research and development. First, for solvate, because the solvent species that can accept in pharmaceutics is limited, and often there is desolventizing (water) phenomenon in solvate in production process, is changed into the worse brilliant type of unstable amorphous or solvability. Secondly, relative to salt, because becoming salt to require, bulk drug has at least the center of an ionization, and each component in medicine eutectic can be neutral molecule, and thus medicine eutectic can contain all API, comprises acid, alkali and non-ionic compound; Further, the potential molecule being used for being formed eutectic with API is also a lot, and these materials may comprise foodstuff additive, sanitas, pharmaceutical excipient, mineral substance, VITAMIN, amino acid and other bioactive molecules, it is even possible that be other API. Generally speaking, eutectic is a kind of solid form having wide application prospects, and preformulation study and dosage form design to medicine have profound influence.
A kind of eutectic is due to its specific crystal habit and specific chemical composition, it is possible to have unique character. Such as, compared with API, eutectic has better pharmacology and pharmacological properties, more easily processes; Eutectic has dissolution rate and the solubleness of the advantage of having more, and human body can be made more to effectively utilize active constituents of medicine, therefore have better bioavailability; Eutectic has better stability in storage. In a word, eutectic may have other the favourable character except result for the treatment of.
Vitamins D (vitaminD) is sterol analog derivative, and tool rickets effect, also known as antirachitic vitamin. It is now recognized that vitamins D is also a kind of steroid hormone, in vitamins D family member, the most important member is D2(ergocalciferol) and D3(cholecalciferol). Vitamins D2(vitaminD2) chemistry be called: 9,10-open loop ergot steroid-5,7,10 (19), 22-tetra-alkene-3-alcohol, its chemical structural formula is as follows:
Vitamins D3(vitaminD3) chemistry be called: 9,10-open loop courage steroid-5,7,10 (19)-triolefin-3-alcohol, its chemical structural formula is as follows:
Vitamins D2And D3In body after liver, kidney metabolism, have and promote that small intestine is to the effect of calcium absorption, can be used as the adjuvant drug of calcium deficiency patient. Due to vitamins D2And D3Instability, to light, thermo-responsive, loses activity after the multi-products such as oxidation and photochemical decomposition in atmosphere.
Summary of the invention
For above shortcomings in prior art, the present invention provides a kind of vitamins D2And D3Eutectic. The present invention adopts on the basis of conformation selectivity cocrystallization, obtains vitamins D2And D3Eutectic. Research finds, vitamins D2With D3The feature that eutectic has degree of crystallinity height, water absorbability is little, and form regular crystal kenel, stability significantly strengthens, and is thus conducive to the art breading of medicine and the improvement of physical and chemical performance, it is to increase patent medicine performance.
Described vitamins D2And D3The chemical structural formula of eutectic be:
Described vitamins D2With D3Eutectic X-ray powder diffraction at 2 �� angle 5.06,6.67,8.63,8.83,10.15,13.47,14.19,15.26,15.64,16.60,17.20,17.90,18.26,21.73,23.46 �� of place has characteristic diffraction peak. More particularly, described vitamins D2With D3Eutectic there is X-ray powder diffraction as shown in Figure 1 substantially.
Described vitamins D2With D3Eutectic be rhombic system, spacer is P212121, unit cell parameters is: ��=��=��=90 ��, unit cell volume is
Described vitamins D2With D3The differential scanning calorimetric analysis of eutectic have feature endotherm(ic)peak at about 97 DEG C.
Vitamins D provided by the invention2With D3Eutectic in, vitamins D2With D3Mol ratio be about 1:1.
Present invention also offers described vitamins D2With D3The preparation method of eutectic, be specially:
By vitamins D2And D3About 1:1 joins in organic solvent in molar ratio, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Described organic solvent comprises all to be had certain solubility and raw material not to cause rotten organic solvent raw material, can one or more for being selected from the organic solvents such as alcohol class, ketone class, nitrile class, ether class, ester class, alkane, aromatic hydrocarbon or halogenated alkane, preferably, described organic solvent is one or more in methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, Nitromethane 99Min., normal hexane, normal heptane, methylene dichloride, methylethylketone, ether, methyl tertiary butyl ether, sherwood oil.
Present invention provides described vitamins D2With D3Eutectic for the preparation for the treatment of calcium deficiency illness medicine in purposes, be more specifically for the preparation of treat rickets, osteomalacia (also referred to as rickets) etc. medicine in purposes.
Present invention provides described vitamins D2With D3Eutectic for the preparation of the purposes of compound calcium preparation, it is preferable that with together with calcium medicine, prepare the purposes in compound calcium preparation.
Present invention also offers a kind of pharmaceutical composition, it comprises described vitamins D2With D3Eutectic and nonessential pharmaceutically acceptable carrier. Described pharmaceutical composition can also comprise containing calcium medicine.
Above-mentioned can be such as calcium carbonate, citrate of lime, bone meal etc. containing calcium medicine.
The vitamins D that the present invention relates to2With D3Eutectic, characterize through the solid-state approach such as X-ray powder diffraction, thermogravimetic analysis (TGA), differential scanning calorimetric analysis.
The preparation method that the present invention relates to is simple to operate, favorable reproducibility, can stablize and obtain target eutectic.
The vitamins D that the present invention relates to2With D3Eutectic, the stability of light and heat is better, can extend shelf life.
Accompanying drawing explanation
Fig. 1. embodiment 1 vitamins D2With D3X-ray powder diffraction (XRPD) figure of eutectic.
Fig. 2. embodiment 1 vitamins D2With D3Thermogravimetic analysis (TGA) (TG) figure of eutectic.
Fig. 3. embodiment 1 vitamins D2With D3Differential scanning calorimetric analysis (DSC) figure of eutectic.
Fig. 4. embodiment 1 vitamins D2With D3Eutectic thermostability comparison figure.
Fig. 5. embodiment 1 vitamins D2With D3Eutectic light stability comparison figure.
Embodiment
The instrument used in the embodiment of the present invention:
X-ray powder diffractometer device:
BrukerD8ADVANCEX x ray diffractometer x, target: CuK �� (40KV, 40mA), sample is to detector distance: 30cm, sweep limit: 3 ��-40 �� (2 �� value), scanning speed: 0.1sec/step, scanning step footpath: 0.02.
Dsc instrument:
PerkinElmer8500DSC, temperature range: 50-200 DEG C, scanning speed: 10 DEG C/min, nitrogen flow rate: 50ml/min.
Thermogravimetic analysis (TGA) testing tool:
NetzschTG209F3, temperature range: 30-400 DEG C, scanning speed: 10 DEG C/min, sweep gas: 25mL/min, protection gas: 15mL/min.
Embodiment 1
By vitamins D2And D3Stoichiometrically 1:1 joins in ethyl acetate, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Fig. 1-3 respectively illustrates embodiment 1 vitamins D2With D3X-ray powder diffraction (XRPD) figure, thermogravimetic analysis (TGA) (TG) figure of eutectic and differential scanning calorimetric analysis (DSC) figure.
Embodiment 2
By vitamins D2And D3Stoichiometrically 1:1 joins in acetone, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Embodiment 3
By vitamins D2And D3Stoichiometrically 1:1 joins in methyl alcohol, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Embodiment 4
By vitamins D2And D3Stoichiometrically 1:1 joins in ethanol, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Embodiment 5
By vitamins D2And D3Stoichiometrically 1:1 joins in toluene, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
Embodiment 6
By vitamins D2And D3Stoichiometrically 1:1 joins in normal hexane, after dissolving completely, slowly volatilizees, obtains vitamins D2With D3Eutectic.
After testing, the vitamins D that embodiment 2-6 obtains2With D3X-ray powder diffraction (XRPD) figure, thermogravimetic analysis (TGA) (TG) figure of eutectic identical with embodiment 1 with differential scanning calorimetric analysis (DSC) figure, namely as Figure 1-3, show that they are same crystal.
Experimental example 7
To the vitamins D of embodiment 1 gained2With D3Eutectic and my fourth reagent (Shanghai) company limited buy vitamins D2And D3Stability difference between bulk drug carries out (1) Acceleration study (40 DEG C/75%RH), (2) illumination experiment (5000Lx).
As shown in Figure 4 and Figure 5, chemical purity adopts HPLC to measure to result, and the method for calculation of purity are area normalization method. Acceleration study is vitamins D after 1 month2And D3Bulk drug becomes yellow solid, and chemical purity is respectively 95.8% and 33.6%, and that the color of the eutectic of embodiment 1, brilliant type and chemical purity all keep is fine, and chemical purity is 99.3%; After illumination experiment investigates 10 days, vitamins D2And D3Bulk drug becomes faint yellow solid, and chemical purity is 45.5% and 88.5%, and that the color of the eutectic of embodiment 1, brilliant type and chemical purity all keep is fine, and chemical purity is 97.2%. Therefore, vitamins D2With D3The commercially available vitamins D of eutectic ratio2Bulk drug and D3Bulk drug chemistry is more stable.
The above; it is only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in disclosed technical scope; the change can expected without creative work or replacement, all should be encompassed within protection scope of the present invention.
Claims (12)
1. a vitamins D2With D3Eutectic, its X-ray powder diffraction is at 2 �� angle 5.06,6.67,8.63,8.83,10.15,13.47,14.19,15.26,15.64,16.60, and 17.20,17.90,18.26,21.73,23.46 �� of place has characteristic diffraction peak.
2. vitamins D according to claim 12With D3Eutectic, it is characterised in that, it has X-ray powder diffraction as shown in Figure 1 substantially.
3. vitamins D according to claim 12With D3Eutectic, it is characterised in that: described vitamins D2With D3Eutectic in vitamins D2With vitamins D3Mol ratio be about 1:1.
4. vitamins D according to claim 12With D3Eutectic, it is characterised in that: described vitamins D2With D3The differential scanning calorimetric analysis of eutectic have feature endotherm(ic)peak at 97 DEG C.
5. vitamins D according to claim 12With D3Eutectic, it is characterised in that: described vitamins D2With D3Eutectic be rhombic system, spacer is P212121, unit cell parameters is: ��=��=��=90 ��, unit cell volume is
6. prepare the vitamins D as according to any one of claim 1-5 for one kind2With D3The method of eutectic, comprise the steps: to be about stoichiometric ratio the vitamins D of 1:12And D3Join in organic solvent, after dissolving completely, slowly volatilize, obtain vitamins D2With D3Eutectic.
7. method according to claim 6, it is characterised in that:
Described organic solvent is one or more that be selected from methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), acetonitrile, ethyl acetate, Nitromethane 99Min., normal hexane, normal heptane, methylene dichloride, methylethylketone, ether, methyl tertiary butyl ether, sherwood oil.
8. vitamins D according to any one of claim 1-52With D3Eutectic for the preparation for the treatment of calcium deficiency illness medicine in purposes.
9. vitamins D according to any one of claim 1-52With D3Eutectic for the preparation for the treatment of rickets or rickets medicine in purposes.
10. vitamins D according to any one of claim 1-52With D3Eutectic for the preparation of the purposes of compound calcium preparation.
11. vitamins Ds according to any one of claim 1-52With D3Eutectic be used for and containing the purposes preparing compound calcium preparation together with calcium medicine.
12. 1 kinds of pharmaceutical compositions, it comprises the vitamins D according to any one of claim 1-52With D3Eutectic and nonessential pharmaceutically acceptable carrier, described pharmaceutical composition can also comprise containing calcium medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410546268.5A CN104356038B (en) | 2014-10-15 | 2014-10-15 | Eutectic of vitamin D2 and D3 and its production and use |
| PCT/CN2015/090212 WO2016058472A1 (en) | 2014-10-15 | 2015-09-22 | Vitamin d2 and vitamin d3 eutectic crystal and preparation method and use thereof |
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| CN201410546268.5A CN104356038B (en) | 2014-10-15 | 2014-10-15 | Eutectic of vitamin D2 and D3 and its production and use |
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| CN104356038B true CN104356038B (en) | 2016-06-01 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019154237A1 (en) * | 2018-02-08 | 2019-08-15 | 中国科学院上海药物研究所 | Co-crystal of calcifediol and vitamin d3, preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104356038B (en) * | 2014-10-15 | 2016-06-01 | 中国科学院上海药物研究所 | Eutectic of vitamin D2 and D3 and its production and use |
| CN109651479B (en) * | 2019-02-15 | 2021-11-16 | 中国科学院上海药物研究所 | Co-crystal of ossifying glycol and cholesterol, preparation method and application thereof |
| CN112999168B (en) * | 2021-03-02 | 2022-11-29 | 天津大学 | Vitamin D 3 Method for preparing amorphous spherical particles |
| CN115181046B (en) * | 2022-07-26 | 2024-01-30 | 中国科学院上海药物研究所 | Eutectic crystal of vitamin D3 and L-menthol as well as preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819379A (en) * | 2014-02-18 | 2014-05-28 | 中国科学院上海药物研究所 | Cholestanol co crystal of vitamin D3 and its preparation method and application |
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| CA2624897C (en) * | 2005-10-12 | 2017-02-14 | Proventiv Therapeutics, Llc | Methods and articles for treating 25-hydroxyvitamin d insufficiency and deficiency |
| CN104356038B (en) * | 2014-10-15 | 2016-06-01 | 中国科学院上海药物研究所 | Eutectic of vitamin D2 and D3 and its production and use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819379A (en) * | 2014-02-18 | 2014-05-28 | 中国科学院上海药物研究所 | Cholestanol co crystal of vitamin D3 and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| Rational Design for Crystallization of β-Lactoglobulin and Vitamin D3 Complex: Revealing a Secondary Binding Site;Ming Chi Yang等;《Crystal Growth & Design》;20081031;第8卷(第12期);4268-4276 * |
| Stabilizing vitamin D3 by conformationally selective co-crystallization;Jian-Rong Wang等;《Chem.Commun.》;20131112;第50卷;855-858 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019154237A1 (en) * | 2018-02-08 | 2019-08-15 | 中国科学院上海药物研究所 | Co-crystal of calcifediol and vitamin d3, preparation method therefor and use thereof |
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| CN104356038A (en) | 2015-02-18 |
| WO2016058472A1 (en) | 2016-04-21 |
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