WO2016058472A1 - 维生素d2与d3的共晶及其制备方法和用途 - Google Patents

维生素d2与d3的共晶及其制备方法和用途 Download PDF

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WO2016058472A1
WO2016058472A1 PCT/CN2015/090212 CN2015090212W WO2016058472A1 WO 2016058472 A1 WO2016058472 A1 WO 2016058472A1 CN 2015090212 W CN2015090212 W CN 2015090212W WO 2016058472 A1 WO2016058472 A1 WO 2016058472A1
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vitamin
eutectic
preparation
crystal
calcium
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French (fr)
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梅雪锋
王建荣
朱冰清
李莎
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中国科学院上海药物研究所
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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
    • 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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  • the invention belongs to the technical field of medicinal chemistry and crystallization technology, and particularly relates to a eutectic of vitamin D 2 and D 3 and a preparation method and use thereof.
  • Co-crystallisation refers to the hydrogenation of pharmaceutically active ingredient (API) molecules with other physiologically acceptable acids, bases, salts, and nonionic compounds, ⁇ - ⁇ stacking, van der Waals forces, and other non-covalent The bonds are connected and combined in the same crystal lattice.
  • API pharmaceutically active ingredient
  • the greatest application value of eutectic in medicine is that it can introduce new components without changing the covalent structure of the drug, and greatly improve the physical and chemical properties of the drug, such as stability, melting point, dissolution rate, dissolution rate, bioavailability, etc.
  • CCF ligands
  • the difference in physical properties exhibited by each new solid form of the active pharmaceutical ingredient affects its storage stability, compressibility and density, as well as solubility and dissolution rate.
  • solvates because of the limited variety of pharmaceutically acceptable solvents, and the solvate often undergoes solvent removal (water) during the formulation process, it is converted to unstable amorphous or less soluble crystals. type.
  • the drug eutectic can cover all APIs, including acid, Alkali and nonionic compounds; and, there are many potential molecules for co-crystal formation with APIs, which may include food additives, preservatives, pharmaceutical excipients, minerals, vitamins, amino acids, and other active molecules, or even Other APIs.
  • APIs including acid, Alkali and nonionic compounds
  • eutectic is a solid form with broad application prospects, which has far-reaching effects on pre-prescription studies and dosage form design of drugs.
  • a eutectic may have unique properties due to its specific crystal morphology and specific chemical composition. For example, compared with API, eutectic has better pharmacological and pharmaceutical properties and is easier to process; eutectic has more advantageous dissolution and solubility, which enables the human body to use medicinal active ingredients more effectively, so it has better Bioavailability; eutectic has better storage stability. In summary, eutectic may have other beneficial properties in addition to therapeutic effects.
  • Vitamin D is a sterol derivative with anti-caries effect, also known as anti-caries vitamin.
  • Vitamin D is currently considered to be a steroid hormone, and the most important members of the vitamin D family members are D 2 (ergocalciferol) and D 3 (cholecalciferol).
  • the chemical name of vitamin D 2 (vitamin D 2 ) is 9,10-open ring ergot-5,7,10(19),22-tetraen-3-ol, and its chemical structural formula is as follows:
  • vitamin D 3 9,10-open-ring cholester-5,7,10(19)-trien-3-ol, the chemical structural formula is as follows:
  • Vitamin D 2 and D 3 have the effect of promoting the absorption of calcium in the small intestine after being metabolized by the liver and kidney in the body, and can be used as an auxiliary medicine for patients with calcium deficiency. Because vitamin D 2 and D 3 are unstable, they are sensitive to light and heat, and lose their activity after being oxidized and photochemically decomposed in air.
  • the present invention provides a eutectic of vitamin D 2 and D 3 .
  • the present invention obtains a co-crystal of vitamin D 2 and D 3 on the basis of conformation-selective co-crystallization. It has been found that the eutectic of vitamin D 2 and D 3 has the characteristics of high crystallinity and low hygroscopicity, and forms a regular crystal form with remarkable stability, which is beneficial to the improvement of the process and physical and chemical properties of the drug. Drug performance.
  • the X-ray powder diffraction pattern of the eutectic of vitamin D 2 and D 3 is at 2 ⁇ angles of 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, There is a characteristic diffraction peak at 23.46°. More particularly, the vitamin D 2 and D 3 eutectic having X- ray powder diffraction pattern substantially as shown in FIG. 1.
  • the present invention provides vitamin D 2 and D eutectic. 3, the molar ratio of vitamin D 2 and D. 3 is about 1: 1.
  • the invention also provides a preparation method of the eutectic of the vitamin D 2 and D 3 , specifically:
  • the vitamin D 2 and D 3 were added to an organic solvent at a molar ratio of about 1:1, and after completely dissolved, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • the organic solvent includes all organic solvents having a certain solubility to the raw materials and not deteriorating the raw materials, and may be selected from organic solvents selected from the group consisting of alcohols, ketones, nitriles, ethers, esters, alkanes, aromatic hydrocarbons or halogenated alkanes.
  • the organic solvent is methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, nitromethane, n-hexane, n-heptane, dichloromethane, methyl ethyl ketone, One or more of diethyl ether, methyl tert-butyl ether, petroleum ether.
  • the present invention also provides the use of the eutectic of vitamin D 2 and D 3 in the preparation of a medicament for treating a calcium deficiency disorder, more particularly in the preparation of a medicament for the treatment of rickets, osteomalacia (also known as cartilage) Use in drugs such as disease).
  • the present invention also provides the use of the eutectic of vitamin D 2 and D 3 for the preparation of a compound calcium preparation, preferably for use in preparing a compound calcium preparation together with a calcium-containing medicine.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the vitamin D 2 and D 3 eutectic and non-essential pharmaceutically acceptable carrier.
  • the pharmaceutical composition may also comprise a calcium containing drug.
  • the calcium-containing drug may be, for example, calcium carbonate, calcium citrate, bone meal or the like.
  • the invention relates to a eutectic of vitamin D 2 and D 3 , which is characterized by solid state methods such as X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry and the like.
  • the preparation method of the invention is simple in operation, good in reproducibility, and stable to obtain a target eutectic.
  • the invention relates to a eutectic of vitamin D 2 and D 3 , which has good stability to heat and light and can prolong the storage period.
  • Example 1 Figure 3 Scanning Calorimetry embodiment vitamin D 2 and D eutectic. 3 shows the differential analysis (DSC) FIG.
  • FIG. 4 Thermal stability control of FIG. 2 with eutectic Example 1 D 3 vitamin D.
  • Example 1 D 2 and vitamin D eutectic light stability control of FIG. 3 embodiment.
  • Bruker D8ADVANCE X-ray diffractometer target: Cu K ⁇ (40KV, 40mA), sample to detector distance: 30cm, scanning range: 3°-40° (2 ⁇ value), scanning rate: 0.1sec/step, scanning step: 0.02.
  • Vitamin D 2 and D 3 were added to ethyl acetate at a stoichiometric ratio of 1:1, and after completely dissolved, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • 1-3 show X-ray powder diffraction (XRPD) patterns, thermogravimetric analysis (TG) patterns, and differential scanning calorimetry (DSC) patterns of the eutectic of vitamin D 2 and D 3 of Example 1.
  • XRPD X-ray powder diffraction
  • TG thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Vitamin D 2 and D 3 were added to acetone at a stoichiometric ratio of 1:1, and after complete dissolution, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • Vitamin D 2 and D 3 were added to methanol at a stoichiometric ratio of 1:1, and after complete dissolution, they were slowly volatilized to obtain a eutectic of vitamin D 2 and D 3 .
  • Vitamin D 2 and D 3 were added to ethanol at a stoichiometric ratio of 1:1, and after completely dissolved, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • Vitamin D 2 and D 3 were added to toluene at a stoichiometric ratio of 1:1, and after completely dissolved, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • Vitamin D 2 and D 3 were added to n-hexane at a stoichiometric ratio of 1:1, and after complete dissolution, they were slowly volatilized to obtain a cocrystal of vitamin D 2 and D 3 .
  • Example 1 is the same, as shown in Figures 1-3, indicating that they are the same crystal.

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Abstract

提供了一种维生素D 2和D 3的共晶、其制备方法和用途，以及包含所述共晶的药物组合物。所述维生素D 2与D 3的共晶具有结晶度高、吸湿性小的优点，并形成规整的晶体型态，稳定性显著增强，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。

Description

维生素D2与D3的共晶及其制备方法和用途 技术领域
本发明属药物化学及结晶工艺技术领域，具体涉及维生素D2与D3的共晶及其制备方法和用途。
背景技术
药物共结晶(共晶)是指药物活性成分(API)分子与其他生理上可接受的酸、碱、盐、非离子化合物分子以氢键、π-π堆积作用、范德华力和其他非共价键相连而结合在同一晶格中。共晶在药物中最大的应用价值就是可以在不改变药物共价结构的同时引入新的组分，大大改善药物的理化性质，如稳定性，熔点、溶解速率、溶出速率、生物利用度等，并且由于配体(CCF)的种类有很多，药物的性质也可以相应得到不同程度的调节。活性药物成分的每一种新的固体形态所表现出来的物理性质的不同会影响其储存稳定性、可压性和密度、以及溶解度和溶出速率。
与盐类、溶剂化物等其他固体形态相比，共晶在药物研发中有着更大的优势。首先，对于溶剂化物来说，因为在药剂学上可以接受的溶剂种类有限，而且溶剂化物在制剂过程中经常发生去溶剂(水)现象，转变为不稳定的无定形或者溶解性更差的晶型。其次，相对于盐来说，因为成盐要求原料药至少有一个离子化的中心，而药物共晶中的各个组分可以是中性分子，因而药物共晶可以涵盖所有的API，包括酸、碱和非离子化合物；并且，潜在的用来和API形成共晶的分子也很多，这些物质可能包括食品添加剂、防腐剂、药用辅料、矿物质、维生素、氨基酸以及其他活性分子，甚至可以是其他的API。总的来说，共晶是一种有广泛应用前景的固体形态，对药物的处方前研究和剂型设计具有深远影响。
一种共晶由于其特定的晶体形态以及特定的化学成分，可能拥有独一无二的性质。比如，与API相比，共晶具有更加良好的药理和制药特性，更容易加工；共晶有更具优势的溶出度和溶解度，能使人体更有效地利用药物活性成分，因此有更好的生物利用度；共晶拥有更好的储存稳定性。总之，共晶可能拥有除了治疗效果以外的其他有利性质。
维生素D(vitamin D)为固醇类衍生物，具抗佝偻病作用，又称抗佝偻病维生素。目前认为维生素D也是一种类固醇激素，维生素D家族成员中最重要的成员是D2(麦角钙化 醇)和D3(胆钙化醇)。维生素D2(vitamin D2)的化学名为：9,10-开环麦角甾-5,7,10(19),22-四烯-3-醇，其化学结构式如下：
Figure PCTCN2015090212-appb-000001
维生素D3(vitamin D3)的化学名为：9,10-开环胆甾-5,7,10(19)-三烯-3-醇，其化学结构式如下：
Figure PCTCN2015090212-appb-000002
维生素D2和D3在体内经肝、肾代谢后，具有促进小肠对钙吸收的作用，可作为缺钙患者的辅助用药。由于维生素D2和D3不稳定，对光、热敏感，在空气中氧化和光化分解等多种产物后失去活性。
发明内容
针对现有技术中存在的上述不足，本发明提供了一种维生素D2和D3的共晶。本发明采用构象选择性共结晶的基础上，获得维生素D2和D3的共晶。研究发现，维生素D2与D3的共晶具有结晶度高、吸湿性小的特点，并形成规整的晶体型态，稳定性显著增强，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。
所述维生素D2和D3的共晶的化学结构式为：
Figure PCTCN2015090212-appb-000003
所述维生素D2与D3的共晶的X-射线粉末衍射图谱中在2θ角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°处具有特征衍射峰。更特别地，所述维生素D2与D3的共晶具有大体上如图1所示的X-射线粉末衍射图谱。
所述维生素D2与D3的共晶为正交晶系，空间群为P212121，晶胞参数为：
Figure PCTCN2015090212-appb-000004
Figure PCTCN2015090212-appb-000005
α＝β＝γ＝90°，晶胞体积为
Figure PCTCN2015090212-appb-000006
所述维生素D2与D3的共晶的差示扫描量热分析在约97℃有特征吸热峰。
本发明提供的维生素D2与D3的共晶中，维生素D2与D3的摩尔比为约1:1。
本发明还提供了所述维生素D2与D3的共晶的制备方法，具体为：
将维生素D2和D3按摩尔比约1:1加入到有机溶剂中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
所述有机溶剂包括所有对原料有一定溶解度且不对原料造成变质的有机溶剂，可以为选自醇类、酮类、腈类、醚类、酯类、烷烃、芳香烃或卤代烷烃等有机溶剂中的一种或多种，优选的，所述有机溶剂为甲醇、乙醇、异丙醇、丙酮、四氢呋喃、乙腈、乙酸乙酯、硝基甲烷、正己烷、正庚烷、二氯甲烷、甲乙酮、乙醚、甲基叔丁基醚、石油醚中的一种或多种。
本发明也提供了所述的维生素D2与D3的共晶在制备用于治疗缺钙病症的药物中的用途，更具体地为在制备用于治疗佝偻病、骨软化症(也称为软骨症)等的药物中的用途。
本发明也提供了所述的维生素D2与D3的共晶用于制备复方钙制剂的用途，优选与含钙药物一起制备复方钙制剂中的用途。
本发明还提供了一种药物组合物，其包含所述的维生素D2与D3的共晶以及非必须的药学上可接受的载体。所述药物组合物还可以包含含钙药物。
上述含钙药物例如可以为碳酸钙、柠檬酸钙、骨粉等。
本发明涉及的维生素D2与D3的共晶，经X-射线粉末衍射、热失重分析、差示扫描量热分析等固态方法表征。
本发明涉及的制备方法操作简单，重现性好，可稳定获得目标共晶体。
本发明涉及的维生素D2与D3的共晶，对热和光的稳定性较好，可延长储存期。
附图说明
图1.实施例1维生素D2与D3的共晶的X-射线粉末衍射(XRPD)图。
图2.实施例1维生素D2与D3的共晶的热失重分析(TG)图。
图3.实施例1维生素D2与D3的共晶的差示扫描量热分析(DSC)图。
图4.实施例1维生素D2与D3的共晶的热稳定性对照图。
图5.实施例1维生素D2与D3的共晶的光稳定性对照图。
具体实施方式
本发明实施例中所使用的仪器：
X-射线粉末衍射仪器：
Bruker D8ADVANCE X射线衍射仪，靶：Cu Kα(40KV，40mA)，样品到检测器距离：30cm，扫描范围：3°-40°(2θ值)，扫描速率：0.1sec/step，扫描步径：0.02。
差示扫描量热法仪器：
Perkin Elmer 8500DSC，温度范围：50-200℃，扫描速率：10℃/min，氮气流速：50ml/min。
热失重分析测试仪器：
Netzsch TG 209F3，温度范围：30-400℃，扫描速率：10℃/min，吹扫气：25mL/min，保护气：15mL/min。
实施例1
将维生素D2和D3按化学计量比1:1加入到乙酸乙酯中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
图1-3分别显示了实施例1维生素D2与D3的共晶的X-射线粉末衍射(XRPD)图、热失重分析(TG)图和差示扫描量热分析(DSC)图。
实施例2
将维生素D2和D3按化学计量比1:1加入到丙酮中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
实施例3
将维生素D2和D3按化学计量比1:1加入到甲醇中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
实施例4
将维生素D2和D3按化学计量比1:1加入到乙醇中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
实施例5
将维生素D2和D3按化学计量比1:1加入到甲苯中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
实施例6
将维生素D2和D3按化学计量比1:1加入到正己烷中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
经检测，实施例2-6获得的维生素D2与D3的共晶的X-射线粉末衍射(XRPD)图、热失重分析(TG)图和差示扫描量热分析(DSC)图与实施例1相同，即如图1-3所示，表明它们为同一种晶体。
实验例7
对实施例1所得的维生素D2与D3的共晶与阿拉丁试剂(上海)有限公司购买的维生素D2和D3原料药之间的稳定性差异进行(1)加速实验(40℃/75％RH)，(2)光照实验(5000Lx)。
结果如图4和图5所示，化学纯度采用HPLC测定，纯度的计算方法为面积归一法。加速实验1个月后维生素D2和D3原料药变成黄色固体，化学纯度分别为95.8％和33.6％，而实施例1的共晶的颜色、晶型和化学纯度都保持的很好，化学纯度为99.3％；光照实验考察10天后，维生素D2和D3原料药变成淡黄色固体，化学纯度为45.5％和88.5％，而实施例1的共晶的颜色、晶型和化学纯度都保持的很好，化学纯度为97.2％。因此，维生素D2与D3的共晶比市售维生素D2原料药和D3原料药化学更稳定。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭示的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种维生素D2与D3的共晶，其X-射线粉末衍射图谱在2θ角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°处具有特征衍射峰。
  2. 根据权利要求1所述的维生素D2与D3的共晶，其特征在于，其具有大体上如图1所示的X-射线粉末衍射图谱。
  3. 根据权利要求1所述的维生素D2与D3的共晶，其特征在于：所述维生素D2与D3的共晶中维生素D2与维生素D3的摩尔比约为1:1。
  4. 根据权利要求1所述的维生素D2与D3的共晶，其特征在于：所述维生素D2与D3的共晶的差示扫描量热分析在97℃有特征吸热峰。
  5. 根据权利要求1所述的维生素D2与D3的共晶，其特征在于：所述维生素D2与D3的共晶为正交晶系，空间群为P212121，晶胞参数为：
    Figure PCTCN2015090212-appb-100001
    Figure PCTCN2015090212-appb-100002
    α＝β＝γ＝90°，晶胞体积为
    Figure PCTCN2015090212-appb-100003
  6. 一种制备如权利要求1-5中任一项所述的维生素D2与D3的共晶的方法，包括如下步骤：将化学计量比约为1:1的维生素D2和D3加入到有机溶剂中，完全溶解后，缓慢挥发，得到维生素D2与D3的共晶。
  7. 根据权利要求6所述的方法，其特征在于：
    所述有机溶剂为选自甲醇、乙醇、异丙醇、丙酮、四氢呋喃、乙腈、乙酸乙酯、硝基甲烷、正己烷、正庚烷、二氯甲烷、甲乙酮、乙醚、甲基叔丁基醚、石油醚中的一种或多种。
  8. 根据权利要求1-5中任一项所述的维生素D2与D3的共晶在制备用于治疗例如佝偻病或软骨症等的缺钙病症的药物中的用途。
  9. 根据权利要求1-5中任一项所述的维生素D2与D3的共晶用于制备复方钙制剂的用途，特别是与含钙药物一起制备复方钙制剂的用途。
  10. 一种药物组合物，其包含权利要求1-5中任一项所述的维生素D2与D3的共晶以及非必须的药学上可接受的载体，所述药物组合物还可以包含含钙药物。
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