WO2022142538A1 - Calcium zoledronate complex and preparation method therefor - Google Patents

Calcium zoledronate complex and preparation method therefor Download PDF

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WO2022142538A1
WO2022142538A1 PCT/CN2021/120982 CN2021120982W WO2022142538A1 WO 2022142538 A1 WO2022142538 A1 WO 2022142538A1 CN 2021120982 W CN2021120982 W CN 2021120982W WO 2022142538 A1 WO2022142538 A1 WO 2022142538A1
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calcium
zoledronic acid
zoledronate
complex
preparation
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施雪涛
壮琛
柴牧原
林佳义
杨夕冉
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华南理工大学
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2430/00—Materials or treatment for tissue regeneration
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the technical field of biomedical materials, in particular to a calcium zoledronate complex and a preparation method thereof.
  • Coordination polymers are a class of compounds formed by the combination of metal ions and organic ligands through coordination bonds.
  • the development of coordination polymer chemistry has given them new exploration and applications in the fields of design, synthesis, structure, and properties, and has gradually become a frontier and hot topic in organic, inorganic, materials, biology, medicine and other disciplines.
  • Using the principle of molecular self-assembly to design and construct complexes with novel structures to make them have specific biological functions has important practical significance for its broad application in the field of biomedicine.
  • Zoledronic acid is a bisphosphonate small molecule drug widely used in clinical anti-osteoporosis, osteoarthritis, bone-related tumors.
  • the current bisphosphonic acid (or sodium salt) is relatively water-soluble, and the concentration threshold for its effective effect is very low, and it is easy to cause adverse reactions when the threshold is exceeded. To a certain extent, it limits the application of molecules with significant osteogenic effects such as bisphosphonates in bone regeneration and repair. Therefore, it is very important to find other bisphosphonates whose solubility or degradation rate is significantly lower than that of bisphosphonates (or sodium salts) for their further promotion and application in the field of bone repair.
  • the bisphosphonic acid structure contains two phosphonate groups, and the ionic forms after ionization in water are mostly bidentate or polydentate ligands, which are easily chelated with multi-coordination metal ions such as calcium ions, forming a kind of stable physical and chemical properties and not easy to Dissolved metal-organic complexes to achieve slow release of bisphosphonic acid molecules in aqueous solutions. Therefore, the complex is bound to have potential applications in the fields of materials science and biomedicine. Therefore, we use zoledronic acid as a ligand to react with calcium ions to prepare calcium zoledronic acid complexes.
  • the preparation method is extremely simple, the crystal growth rate is moderate, the stress is small, the uniformity is good, and it has a very complete shape, which is not easy to dissolve. In water, it has important potential applications in the fields of drug sustained release, targeted delivery and bone tissue repair.
  • the purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art, and propose a calcium zoledronate complex and a preparation method thereof.
  • the calcium complex of zoledronate prepared by the standing method has a very simple preparation method, The crystal growth rate is moderate, the stress is small, the uniformity is good and the shape is very complete, and it has important potential application prospects in the fields of drug sustained release, targeted delivery and bone tissue repair.
  • the present invention also provides a method for preparing the above-mentioned calcium zoledronic acid complex.
  • the method uses calcium salt and zoledronic acid as raw materials, uses deionized water as solvent, and uses sodium hydroxide solution to adjust pH to 4-5, Stand for 3-30 days at 20-200°C, then filter, wash and dry to obtain flat rectangular transparent crystals, which are calcium zoledronate complexes; wherein, the reaction time and reaction temperature are negatively correlated, that is, the temperature The higher it is, the shorter the reaction time.
  • the concentration of the zoledronic acid is 3-20 mmol/L.
  • the molar ratio of the calcium salt and zoledronic acid is 1:2-2:1.
  • the calcium salt is any one of calcium chloride, calcium nitrate and calcium hydroxide.
  • the present invention has the following advantages and beneficial effects:
  • the present invention uses calcium salt and zoledronic acid as raw materials to prepare the calcium complex of zoledronic acid by the standing method.
  • the complex has calcium as the central atom and zoledronic acid as the bridging ligand, presenting a one-dimensional linear structure in space.
  • the zoledronic acid calcium complex has important potential application prospects in the fields of drug sustained release, targeted delivery, and bone tissue repair, and is worthy of promotion.
  • Figure 1 is a crystal diagram of a calcium zoledronate complex.
  • Figure 2 is a structural unit diagram of a calcium zoledronate complex.
  • Figure 3 is a thermogravimetric curve of a calcium zoledronate complex.
  • the reaction time of the preparation process is negatively correlated with the reaction temperature, that is, the higher the temperature, the shorter the reaction time;
  • the morphology of the prepared calcium zoledronate complex in the aqueous solution is a flat rectangular transparent crystal, and with the increase of pH Raised, the rectangle gets smaller and smaller.
  • Fig. 1 is an optical microscope image of a crystal of calcium zoledronate complex, and it can be seen from the figure that the calcium complex of zoledronate is a flat rectangular transparent crystal.
  • the central metal calcium atom is six-coordinated, which is coordinated with 5 O (2+3, respectively from two zoledronic acid ligands) and 1 O (from water ligand) to form an octahedral structure.
  • One of the O atoms is coordinated with two Ca atoms at the same time, acting as a bridge, so that the Ca atoms are arranged in a one-dimensional linear chain in space.
  • thermogravimetric curve of the complex As shown in Figure 3. It can be seen from the figure that the delattice water temperature of the calcium zoledronate complex is above 100 °C, The decomposition temperature exceeds 300°C, indicating that the complex has good thermal stability.

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Abstract

Disclosed in the present invention are a calcium zoledronate complex and a preparation method therefor, the chemical formula thereof being Ca(Zol)(H2O)·2H2O, wherein Ca represents calcium, Zol represents zoledronate, and H2O represents water, the crystal system being a monoclinic system, the space group being P21/N, the lattice constants being a = 6.8594Å, b = 6.737Å, c = 27.345Å, v = 1257.30Å3, β = 95.753°, and z = 4. The method comprises using calcium salt and zoledronate as raw materials and deionised water as a solvent, using a sodium hydroxide solution to adjust the pH to 4-5, standing for 3-30 days at 20-200℃, and then filtering, washing, and drying to obtain a flat rectangular transparent crystal, i.e. the calcium zoledronate complex. The preparation method of the present invention is extremely simple, and the crystal has a moderate growth rate, low stress, good uniformity, and a very complete shape, having important potential application prospects in the fields of the slow release and targeted delivery of drugs and bone tissue repair.

Description

一种唑来膦酸钙配合物及其制备方法A kind of zoledronic acid calcium complex and preparation method thereof 技术领域technical field
本发明涉及生物医学材料的技术领域，尤其是指一种唑来膦酸钙配合物及其制备方法。The invention relates to the technical field of biomedical materials, in particular to a calcium zoledronate complex and a preparation method thereof.
背景技术Background technique
配位聚合物是一类由金属离子和有机配体通过配位键结合形成的化合物。近年来，配位聚合物化学的发展赋予其在设计、合成、结构、性能等领域新的探索与应用，逐渐成为有机、无机、材料、生物、医学等学科的前沿和热点课题。利用分子自组装原理来设计和构筑具有新颖结构的配合物，使其具有特定的生物学功能，对其在生物医学领域广阔的应用具有重要的现实意义。Coordination polymers are a class of compounds formed by the combination of metal ions and organic ligands through coordination bonds. In recent years, the development of coordination polymer chemistry has given them new exploration and applications in the fields of design, synthesis, structure, and properties, and has gradually become a frontier and hot topic in organic, inorganic, materials, biology, medicine and other disciplines. Using the principle of molecular self-assembly to design and construct complexes with novel structures to make them have specific biological functions has important practical significance for its broad application in the field of biomedicine.
唑来膦酸是一种广泛应用于临床上抗骨质疏松、变形性骨炎、骨相关肿瘤的双膦酸类小分子药物。但是，当前双膦酸(或钠盐)水溶性比较强，而其发挥有效作用的浓度阈值很低，超过阈值容易引发不良反应，因而通常只能进行直接注射或使用递送系统进行负载缓释，一定程度上限制了双膦酸盐这类成骨效果显著的分子在骨再生修复中的应用。因而，寻找显著低于双膦酸(或钠盐)的溶解度或降解速率的其它双膦酸盐对于其在骨修复领域进一步推广应用具有非常重要的意义。Zoledronic acid is a bisphosphonate small molecule drug widely used in clinical anti-osteoporosis, osteoarthritis, bone-related tumors. However, the current bisphosphonic acid (or sodium salt) is relatively water-soluble, and the concentration threshold for its effective effect is very low, and it is easy to cause adverse reactions when the threshold is exceeded. To a certain extent, it limits the application of molecules with significant osteogenic effects such as bisphosphonates in bone regeneration and repair. Therefore, it is very important to find other bisphosphonates whose solubility or degradation rate is significantly lower than that of bisphosphonates (or sodium salts) for their further promotion and application in the field of bone repair.
双膦酸结构含有两个膦酸根，在水中电离后的离子形态大多是两齿或多齿配体，极易与钙离子等多配位金属离子螯合，形成一类物理化学性质稳定且不易溶解的金属有机配合物，从而实现双膦酸分子在水溶液中的缓慢释放。因此，该配合物势必在材料科学和生物医学等领域具有潜在的应用价值。所以我们以唑来膦酸为配体和钙离子反应，制得唑来膦酸钙配合物，制备方法极为简单，晶体生长速度适中，应力小，均匀性好且具有非常完整的外形，不易溶解在水中，在药物缓释，靶向输运及骨组织修复等领域都具有重要的潜在应用前景。The bisphosphonic acid structure contains two phosphonate groups, and the ionic forms after ionization in water are mostly bidentate or polydentate ligands, which are easily chelated with multi-coordination metal ions such as calcium ions, forming a kind of stable physical and chemical properties and not easy to Dissolved metal-organic complexes to achieve slow release of bisphosphonic acid molecules in aqueous solutions. Therefore, the complex is bound to have potential applications in the fields of materials science and biomedicine. Therefore, we use zoledronic acid as a ligand to react with calcium ions to prepare calcium zoledronic acid complexes. The preparation method is extremely simple, the crystal growth rate is moderate, the stress is small, the uniformity is good, and it has a very complete shape, which is not easy to dissolve. In water, it has important potential applications in the fields of drug sustained release, targeted delivery and bone tissue repair.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于克服现有技术的缺点与不足，提出了一种唑来膦酸钙配合物及其制备方法，通过静置法制备得到的唑来膦酸钙配合物，制备方法极为简单，晶体生长速度适中，应力小，均匀性好且具有非常完整的外形，在药物缓释、靶向输运及骨组织修复等领域都具有重要的潜在应用前景。The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art, and propose a calcium zoledronate complex and a preparation method thereof. The calcium complex of zoledronate prepared by the standing method has a very simple preparation method, The crystal growth rate is moderate, the stress is small, the uniformity is good and the shape is very complete, and it has important potential application prospects in the fields of drug sustained release, targeted delivery and bone tissue repair.
为实现上述目的，本发明所提供的技术方案为：一种唑来膦酸钙配合物，其化学式为Ca(Zol)(H 2O)·2H 2O，其中Ca表示钙，Zol表示唑来膦酸，H 2O表示水，晶系为单斜晶系，空间群为P2 1/N，晶格常数为
Figure PCTCN2021120982-appb-000001
Figure PCTCN2021120982-appb-000002
β＝95.753°，z＝4。 In order to achieve the above purpose, the technical solution provided by the present invention is: a calcium zoledronic acid complex, the chemical formula of which is Ca(Zol)(H 2 O)·2H 2 O, wherein Ca represents calcium, and Zol represents zoledronic acid Phosphonic acid, H 2 O represents water, the crystal system is monoclinic, the space group is P2 1 /N, and the lattice constant is
Figure PCTCN2021120982-appb-000001
Figure PCTCN2021120982-appb-000002
β=95.753°, z=4.
进一步，其在水溶液中形貌为无色透明扁平矩形，且随着pH的升高，矩形越来越小。Furthermore, its morphology in aqueous solution is a colorless and transparent flat rectangle, and with the increase of pH, the rectangle becomes smaller and smaller.
本发明也提供了上述唑来膦酸钙配合物的制备方法，该方法是以钙盐和唑来膦酸为原料，以去离子水为溶剂，用氢氧化钠溶液调节pH至4-5，于20-200℃下静置3-30天，再过滤、洗涤和干燥，得到扁平矩形状透明晶体，即为唑来膦酸钙配合物；其中，反应时间和反应温度呈负相关，即温度越高，反应时间越短。The present invention also provides a method for preparing the above-mentioned calcium zoledronic acid complex. The method uses calcium salt and zoledronic acid as raw materials, uses deionized water as solvent, and uses sodium hydroxide solution to adjust pH to 4-5, Stand for 3-30 days at 20-200°C, then filter, wash and dry to obtain flat rectangular transparent crystals, which are calcium zoledronate complexes; wherein, the reaction time and reaction temperature are negatively correlated, that is, the temperature The higher it is, the shorter the reaction time.
进一步，所述唑来膦酸的浓度为3-20mmol/L。Further, the concentration of the zoledronic acid is 3-20 mmol/L.
进一步，所述钙盐和唑来膦酸的摩尔比为1:2～2:1。Further, the molar ratio of the calcium salt and zoledronic acid is 1:2-2:1.
进一步，所述钙盐为氯化钙、硝酸钙、氢氧化钙中的任意一种。Further, the calcium salt is any one of calcium chloride, calcium nitrate and calcium hydroxide.
本发明与现有技术相比，具有如下优点与有益效果：Compared with the prior art, the present invention has the following advantages and beneficial effects:
本发明以钙盐和唑来膦酸为原料，采用静置法制备的唑来膦酸钙配合物，制备方法极为简单，晶体生长速度适中，应力小，均匀性好且具有非常完整的外形。该配合物以钙为中心原子，唑来膦酸为桥连配体，呈现空间一维直链状 结构。该唑来膦酸钙配合物在药物缓释、靶向输运及骨组织修复等领域都具有重要的潜在应用前景，值得推广。The present invention uses calcium salt and zoledronic acid as raw materials to prepare the calcium complex of zoledronic acid by the standing method. The complex has calcium as the central atom and zoledronic acid as the bridging ligand, presenting a one-dimensional linear structure in space. The zoledronic acid calcium complex has important potential application prospects in the fields of drug sustained release, targeted delivery, and bone tissue repair, and is worthy of promotion.
附图说明Description of drawings
图1为唑来膦酸钙配合物的晶体图。Figure 1 is a crystal diagram of a calcium zoledronate complex.
图2为唑来膦酸钙配合物的结构单元图。Figure 2 is a structural unit diagram of a calcium zoledronate complex.
图3为唑来膦酸钙配合物的热重曲线。Figure 3 is a thermogravimetric curve of a calcium zoledronate complex.
具体实施方式Detailed ways
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。The present invention will be described in further detail below with reference to the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.
实施例1Example 1
称取纯度为98％的唑来膦酸(0.0082g，0.03mmol)、纯度为98％的氯化钙(0.0033g，0.03mmol)，加入10mL水中，缓慢滴入0.1mol/L NaOH溶液，同时搅拌使溶液澄清透明并调节pH至4，然后将溶液转移到西林瓶中，盖好，拧紧，将西林瓶置于恒温箱中，于20℃下反应30天，随后过滤，洗涤，干燥，得到较大的形状规则的扁平矩形状透明晶体，即为唑来膦酸钙配合物。其中，制备过程的反应时间和反应温度呈负相关，即温度越高，反应时间越短；制备的唑来膦酸钙配合物在水溶液中形貌为扁平矩形状透明晶体，且随着pH的升高，矩形越来越小。Weigh 98% pure zoledronic acid (0.0082g, 0.03mmol) and 98% pure calcium chloride (0.0033g, 0.03mmol), add 10mL of water, slowly drop 0.1mol/L NaOH solution, and simultaneously Stir to make the solution clear and transparent and adjust the pH to 4, then transfer the solution to a vial, cap it, screw it tightly, place the vial in an incubator, react at 20°C for 30 days, then filter, wash, and dry to obtain Larger and regular flat rectangular transparent crystals are calcium zoledronate complexes. Among them, the reaction time of the preparation process is negatively correlated with the reaction temperature, that is, the higher the temperature, the shorter the reaction time; the morphology of the prepared calcium zoledronate complex in the aqueous solution is a flat rectangular transparent crystal, and with the increase of pH Raised, the rectangle gets smaller and smaller.
图1为唑来膦酸钙配合物晶体的光学显微镜图，从图中可以看出该唑来膦酸钙配合物为扁平矩形状透明晶体。Fig. 1 is an optical microscope image of a crystal of calcium zoledronate complex, and it can be seen from the figure that the calcium complex of zoledronate is a flat rectangular transparent crystal.
对唑来膦酸钙晶体进行单晶测试及解析，得到该配合物的结构单元图，如图2所示，该唑来膦酸钙配合物的化学式为Ca(Zol)(H 2O)·2H 2O，其中Ca表示钙，Zol表示唑来膦酸，H 2O表示水，晶系为单斜晶系，空间群为P2 1/N，晶格 常数为
Figure PCTCN2021120982-appb-000003
β＝95.753°，z＝4。中心金属钙原子为六配位，分别与5个O(2+3，分别来自两个唑来膦酸配体)和1个O(来自水配体)配位，形成八面体结构。其中一个O原子同时与两个Ca原子配位，起桥连作用，使得Ca原子在空间以一维直链排列。 The single crystal test and analysis of calcium zoledronate crystals were carried out, and the structural unit diagram of the complex was obtained. As shown in Figure 2, the chemical formula of the calcium zoledronate complex is Ca(Zol)(H 2 O)· 2H 2 O, where Ca represents calcium, Zol represents zoledronic acid, H 2 O represents water, the crystal system is monoclinic, the space group is P2 1 /N, and the lattice constant is
Figure PCTCN2021120982-appb-000003
β=95.753°, z=4. The central metal calcium atom is six-coordinated, which is coordinated with 5 O (2+3, respectively from two zoledronic acid ligands) and 1 O (from water ligand) to form an octahedral structure. One of the O atoms is coordinated with two Ca atoms at the same time, acting as a bridge, so that the Ca atoms are arranged in a one-dimensional linear chain in space.
对唑来膦酸钙晶体进行热力学分析，得到该配合物的热重曲线，如图3所示，由图可以看出，唑来膦酸钙配合物的脱晶格水温度在100℃以上，分解温度超过300℃，表明此配合物有很好的热稳定性。The thermodynamic analysis of calcium zoledronate crystals was carried out to obtain the thermogravimetric curve of the complex, as shown in Figure 3. It can be seen from the figure that the delattice water temperature of the calcium zoledronate complex is above 100 °C, The decomposition temperature exceeds 300℃, indicating that the complex has good thermal stability.
实施例2Example 2
称取纯度为98％的唑来膦酸(0.0136g，0.05mmol)、纯度为98％的氢氧化钙(0.0074g，0.1mmol)，加入10mL水中，缓慢滴入0.1mol/L NaOH溶液，同时搅拌使溶液澄清透明并调节pH至4，然后将溶液转移到西林瓶中，盖好，拧紧，将西林瓶置于恒温箱中，于80℃下反应20天，随后过滤，洗涤，干燥，得到较大的形状规则的扁平矩形状透明晶体，即为唑来膦酸钙配合物。Weigh 98% pure zoledronic acid (0.0136g, 0.05mmol) and 98% pure calcium hydroxide (0.0074g, 0.1mmol), add 10mL of water, slowly drop 0.1mol/L NaOH solution, and simultaneously Stir to make the solution clear and transparent and adjust the pH to 4, then transfer the solution to a vial, cap it, screw it tightly, place the vial in an incubator, react at 80°C for 20 days, then filter, wash, and dry to obtain Larger and regular flat rectangular transparent crystals are calcium zoledronate complexes.
实施例3Example 3
称取纯度为98％的唑来膦酸(0.0272g，0.1mmol)、纯度为98％的硝酸钙(0.0082g，0.05mmol)，加入10mL水中，缓慢滴入0.1mol/L NaOH溶液，同时搅拌使溶液澄清透明并调节pH至5，然后将溶液转移到15mL反应釜中，盖好，拧紧，将反应釜置于恒温箱中，于150℃下反应7天，随后过滤，洗涤，干燥，得到适中的形状规则的扁平矩形状透明晶体，即为唑来膦酸钙配合物。Weigh 98% pure zoledronic acid (0.0272 g, 0.1 mmol) and 98% pure calcium nitrate (0.0082 g, 0.05 mmol), add 10 mL of water, slowly drop 0.1 mol/L NaOH solution, while stirring Make the solution clear and transparent and adjust the pH to 5, then transfer the solution to a 15mL reaction kettle, cover it, screw it tightly, place the reaction kettle in a thermostat, react at 150°C for 7 days, then filter, wash, and dry to obtain Moderately shaped and regular flat rectangular transparent crystals are calcium zoledronate complexes.
实施例4Example 4
称取纯度为98％的唑来膦酸(0.0408g，0.15mmol)、纯度为98％的氯化钙(0.0166g，0.15mmol)，加入10mL水中，缓慢滴入0.1mol/L NaOH溶液，同时搅拌使溶液澄清透明并调节pH至5，然后将溶液转移到15mL反应釜中，盖好， 拧紧，将反应釜置于恒温箱中，于200℃下反应3天，随后过滤，洗涤，干燥，得到适中的形状规则的扁平矩形状透明晶体，即为唑来膦酸钙配合物。Weigh 98% pure zoledronic acid (0.0408g, 0.15mmol), 98% pure calcium chloride (0.0166g, 0.15mmol), add 10mL of water, slowly drop 0.1mol/L NaOH solution, and simultaneously Stir to make the solution clear and transparent and adjust the pH to 5, then transfer the solution to a 15mL reaction kettle, cover it, screw it tightly, place the reaction kettle in a thermostat, react at 200 ° C for 3 days, then filter, wash, dry, A moderately shaped and regular flat rectangular transparent crystal is obtained, which is the calcium zoledronate complex.
实施例5Example 5
称取纯度为98％的唑来膦酸(0.0544g，0.20mmol)、纯度为98％的氯化钙(0.0222g，0.20mmol)，加入10mL水中，缓慢滴入0.1mol/L NaOH溶液，同时搅拌使溶液澄清透明并调节pH至4，然后将溶液转移到15mL反应釜中，盖好，拧紧，将反应釜置于恒温箱中，于200℃下反应3天，随后过滤，洗涤，干燥，得到较小的形状规则的扁平矩形状透明晶体，即为唑来膦酸钙配合物。Weigh 98% pure zoledronic acid (0.0544g, 0.20mmol) and 98% pure calcium chloride (0.0222g, 0.20mmol), add 10mL of water, slowly drop 0.1mol/L NaOH solution, and simultaneously Stir to make the solution clear and transparent and adjust the pH to 4, then transfer the solution to a 15mL reaction kettle, cover, tighten, place the reaction kettle in a thermostat, react at 200 ° C for 3 days, then filter, wash, dry, Smaller and regular flat rectangular transparent crystals are obtained, which are calcium zoledronate complexes.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (6)

  1. 一种唑来膦酸钙配合物，其特征在于，其化学式为Ca(Zol)(H 2O)·2H 2O，其中Ca表示钙，Zol表示唑来膦酸，H 2O表示水，晶系为单斜晶系，空间群为P2 1/N，晶格常数为
    Figure PCTCN2021120982-appb-100001
    β＝95.753°，z＝4。     A calcium zoledronic acid complex, characterized in that its chemical formula is Ca(Zol)(H 2 O) 2H 2 O, wherein Ca represents calcium, Zol represents zoledronic acid, H 2 O represents water, and crystal The system is monoclinic, the space group is P2 1 /N, and the lattice constant is
    Figure PCTCN2021120982-appb-100001
    β=95.753°, z=4.
  2. 根据权利要求1所述的一种唑来膦酸钙配合物，其特征在于：其在纯水溶液中形貌为无色透明扁平矩形，且随着pH的升高，矩形越来越小。The calcium zoledronate complex according to claim 1, characterized in that: its appearance in the pure aqueous solution is a colorless, transparent, flat rectangle, and with the increase of pH, the rectangle becomes smaller and smaller.
  3. 一种权利要求1所述唑来膦酸钙配合物的制备方法，其特征在于：该方法是以钙盐和唑来膦酸为原料，以去离子水为溶剂，用氢氧化钠溶液调节pH至4-5，于20-200℃下静置3-30天，再过滤、洗涤和干燥，得到扁平矩形状透明晶体，即为唑来膦酸钙配合物；其中，反应时间和反应温度呈负相关，即温度越高，反应时间越短。A method for preparing calcium zoledronic acid complex according to claim 1, characterized in that: the method takes calcium salt and zoledronic acid as raw materials, takes deionized water as a solvent, and adjusts pH with sodium hydroxide solution To 4-5, let stand at 20-200 ℃ for 3-30 days, and then filter, wash and dry to obtain flat rectangular transparent crystals, namely zoledronic acid calcium complex; wherein, the reaction time and reaction temperature are in the form of Negative correlation, that is, the higher the temperature, the shorter the reaction time.
  4. 根据权利要求3所述的一种唑来膦酸钙配合物的制备方法，其特征在于：所述唑来膦酸的浓度为3-20mmol/L。The preparation method of a calcium zoledronic acid complex according to claim 3, wherein the concentration of the zoledronic acid is 3-20 mmol/L.
  5. 根据权利要求3所述的一种唑来膦酸钙配合物的制备方法，其特征在于：所述钙盐和唑来膦酸的摩尔比为1:2～2:1。The preparation method of a calcium zoledronic acid complex according to claim 3, wherein the molar ratio of the calcium salt and the zoledronic acid is 1:2 to 2:1.
  6. 根据权利要求3或5所述的一种唑来膦酸钙配合物的制备方法，其特征在于：所述钙盐为氯化钙、硝酸钙、氢氧化钙中的任意一种。The preparation method of a calcium zoledronate complex according to claim 3 or 5, wherein the calcium salt is any one of calcium chloride, calcium nitrate and calcium hydroxide.
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