WO2020088479A1 - 一种利用水溶液制备单晶或无定型物的方法 - Google Patents

一种利用水溶液制备单晶或无定型物的方法 Download PDF

Info

Publication number
WO2020088479A1
WO2020088479A1 PCT/CN2019/114136 CN2019114136W WO2020088479A1 WO 2020088479 A1 WO2020088479 A1 WO 2020088479A1 CN 2019114136 W CN2019114136 W CN 2019114136W WO 2020088479 A1 WO2020088479 A1 WO 2020088479A1
Authority
WO
WIPO (PCT)
Prior art keywords
single crystal
freezing
pseudo
substance
aqueous solution
Prior art date
Application number
PCT/CN2019/114136
Other languages
English (en)
French (fr)
Inventor
王健君
范庆瑞
周昕
吕健勇
Original Assignee
中国科学院化学研究所
中国科学院大学
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 中国科学院化学研究所, 中国科学院大学 filed Critical 中国科学院化学研究所
Publication of WO2020088479A1 publication Critical patent/WO2020088479A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • C30B7/08—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by cooling of the solution

Definitions

  • the invention relates to the field of preparation of single crystals or amorphous materials, in particular to a method for preparing single crystals or amorphous materials using an aqueous solution.
  • the method is applicable to the preparation of any water-soluble molecular single crystals or amorphous materials.
  • Single crystals play an important role in various modern scientific fields, such as organic molecular and protein structure analysis, optoelectronic devices, medicine and aerospace.
  • molecular crystallization methods have been extensively studied, and commonly used solvents are slow evaporation method, cooling method, liquid phase diffusion method, polymer induced crystallization and gas phase diffusion method.
  • the above-mentioned methods generally have problems such as poor controllability of crystal nucleation and growth, difficulty in growing single crystals, and easy occurrence of polycrystals.
  • Some molecules cannot even obtain single crystals using the above method, so how to efficiently prepare a perfect single crystal is still a huge challenge.
  • some amorphous materials also play an important role in the field of science.
  • the present invention provides a method for preparing a single crystal or an amorphous substance using an aqueous solution.
  • a method for preparing single crystal or amorphous material using an aqueous solution includes the following steps:
  • step (a2) freezing the aqueous solution of the pseudo-crystalline substance in step (a1);
  • step (a3) a mixed system of the single crystal or amorphous substance of the pseudo-crystalline substance in step (a2) and ice is separated to obtain the single crystal or amorphous substance of the pseudo-crystalline substance.
  • step (a1) in step (a1)
  • the water includes but is not limited to ultrapure water, secondary water, and deionized water.
  • the pseudo-crystalline material includes, but is not limited to, inorganic substances and / or organic substances.
  • the solubility of the pseudo-crystalline substance in water is insoluble, slightly soluble, soluble or easily soluble.
  • step (a2) specifically includes the following steps:
  • the aqueous solution of the pseudo-crystalline substance in step (a1) is cooled and frozen into a solid mixture, and optionally subjected to aging treatment to prepare a mixed system of single crystal or amorphous substance containing pseudo-crystalline substance and ice.
  • step (a2) the freezing is to convert the aqueous solution of the pseudo-crystalline substance in step (a1) from liquid to solid.
  • the freezing method includes but is not limited to compression refrigeration equipment cooling freezing, semiconductor refrigeration equipment cooling freezing, liquid nitrogen cooling freezing, liquid helium cooling freezing, liquid carbon dioxide cooling freezing, liquid oxygen cooling freezing, liquid ethane cooling freezing , Dry ice cooling and freezing, ice cooling and freezing, one or a combination of several methods of cooling and freezing.
  • the freezing process includes, but is not limited to, one or a combination of several types of freezing processes: rapid cooling, slow cooling, stepwise cooling, first heating and then cooling.
  • the freezing includes but is not limited to complete freezing and incomplete freezing.
  • the aging means that the aqueous solution that maintains the pseudo-crystalline substance remains frozen for a period of time.
  • the aging time refers to the time required to raise or lower the temperature to the aging temperature after the freezing process ends, and the time maintained at the aging temperature.
  • the solution of the pseudo-crystalline substance in the step (a1) is frozen to prepare a mixed system of single crystal and ice containing the pseudo-crystalline substance.
  • the step (a2) includes a aging treatment step, that is, in the step (a2), the solution of the pseudo-crystalline substance in the step (a1) is frozen and matured to prepare a pseudo-crystalline substance-containing substance.
  • a aging treatment step that is, in the step (a2), the solution of the pseudo-crystalline substance in the step (a1) is frozen and matured to prepare a pseudo-crystalline substance-containing substance.
  • the temperature is raised to a certain temperature at a temperature increase or decrease rate of 10 ° C./min or more, and the curing time is less than 25 min.
  • a temperature increase or decrease rate of 10 ° C./min or more
  • the curing time is less than 25 min.
  • the greater the difference between the temperature reached and the freezing temperature the larger the particle size of the resulting amorphous material. Therefore, the particle size of the obtained amorphous substance can be controlled by adjusting the size of the temperature difference.
  • the temperature is raised to a certain temperature at a heating or cooling rate of less than 10 ° C / min, and / or the curing time is at least 25 min to prepare A mixed system of single crystals containing quasi-crystalline substances and ice.
  • the temperature is raised to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min for a period of time to prepare a mixed system of a single crystal containing ice to be crystallized and ice.
  • the temperature is increased to a certain temperature at an arbitrary heating or cooling rate, and the aging is performed for at least 25 minutes to prepare a mixed system of single crystals and ice containing pseudo-crystalline substances.
  • the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min, and the aging is performed for at least 25 minutes to prepare a mixed system of single crystals and ice containing pseudo-crystalline substances.
  • the separation uses a physical method and / or a chemical method to separate the single crystal from the ice.
  • the physical means include but are not limited to one or a combination of mechanical separation and sublimation (such as vacuum sublimation).
  • the chemical methods include but are not limited to one or a combination of several methods in chemical reaction and electrolysis.
  • the method further includes the following steps:
  • step (a4) The single crystal or amorphous prepared in step (a3).
  • the collection includes, but is not limited to, one or a combination of optical microscope collection, scanning electron microscope collection, dual-beam electron microscope collection, and transmission electron microscope collection.
  • the invention also provides a method for cultivating a single crystal, the method including the above-mentioned method for preparing a single crystal.
  • the method for cultivating a single crystal further includes the following steps:
  • step (b2) Collect the single crystal cultivated in step (b1).
  • the transferring may be transferring the mixed system of the single crystal containing the pseudo-crystal substance and ice of step (a2) to the mother liquid of the pseudo-crystal substance for single crystal cultivation; or the step (a3) )
  • the single crystal after ice removal is directly transferred to the mother liquid of the pseudo-crystalline material for single crystal cultivation; or the single crystal collected in step (a4) is transferred to the mother liquid of the pseudo-crystalline material for single crystal cultivation.
  • the transfer includes but is not limited to one or a combination of optical microscope removal, scanning electron microscope removal, dual-beam electron microscope removal, and transmission electron microscope removal.
  • the method for cultivating the single crystal includes, but is not limited to, one or a combination of evaporation method, cooling method, and diffusion method.
  • the collection includes, but is not limited to, one or a combination of optical microscope collection, scanning electron microscope collection, dual-beam electron microscope collection, and transmission electron microscope collection.
  • the present invention proposes for the first time a method for controlling the nucleation and crystallization of solute molecules by freezing the aqueous solution. Crystallization of dissolved solute molecules is achieved in the process of water crystallization, and the use of regulation of the freezing of the aqueous solution, and optionally the aging process, quickly and efficiently prepare single crystals or amorphous solute molecules. At the same time, it solves the problem of single crystal preparation which is difficult to crystallize molecules in the traditional single crystal preparation and cultivation process. It can also solve the problem that some substances are difficult to form amorphous, especially high-purity amorphous, which is universal.
  • the present invention also has the characteristics of obtaining a single crystal or amorphous substance of a pseudo-crystalline substance in a short time (a few minutes to several hours).
  • freezing the solution is a key technical point.
  • the freezing process refers to freezing the aqueous solution in an arbitrary manner, and the freezing time, freezing temperature, freezing temperature gradient, freezing method, freezing process, etc. are not particularly limited.
  • the experiment confirmed that the essence of preparing solute single crystal or amorphous by freezing in aqueous solution is that during the freezing process, while water molecules form ice crystals, the solute molecules will be released and gather at the ice crystal interface.
  • the aging process in the present invention refers to keeping the frozen aqueous solution in a solid state for a certain period of time.
  • the temperature is not limited, but the rate of temperature increase or decrease needs to be controlled.
  • the aging process described in the present invention can optionally be used as a supplement to the freezing process to optimize the regulation of the ice crystal recrystallization process, thereby regulating the release rate of solute molecules in the ice crystal and the aggregation rate of solute molecules to the ice crystal interface It is beneficial to further optimize the growth of amorphous and nucleation and growth of single crystal after the solution is frozen.
  • the curing process does not have too much limit on the temperature, and the frozen system does not need to continue to freeze but can undergo the curing process to obtain single crystals or amorphous particles with a particle size in the range of nanometers to micrometers, which is beneficial to the selection of At a more economical temperature, the optimized preparation of single crystals or amorphous materials with higher efficiency is conducive to the reduction of energy consumption and great cost savings.
  • the invention realizes the optimal regulation of ice crystal recrystallization by regulating the heating or cooling rate during the aging process, which can further regulate the aggregation speed of the solute molecules in the ice crystal to the interface of the ice crystal, thereby effectively obtaining the solute molecule single Crystal or amorphous, it has the advantages of saving energy and improving efficiency, which is more conducive to large-scale industrial production.
  • the preparation method and further cultivation method of the single crystal or amorphous material provided by the present invention have a wide range of applications, and are applicable to both existing inorganic and organic materials.
  • the method can also be used to achieve the traditional method that is difficult to crystallize Acquisition of single crystal or amorphous substance.
  • the experimental method is simple and operable.
  • the method of the present invention is not only applicable in laboratory basic research, but also meets the needs of industrial production.
  • Figure 1 is a scanning electron micrograph of copper sulfate single crystals prepared in Examples 1, 2, and 3.
  • Figure 2 is a scanning electron micrograph of glutamic acid single crystals prepared in Examples 4, 7, 8, and 9.
  • Figure 3 is a scanning electron micrograph of the benzyl penicillin single crystal prepared in Examples 5 and 6.
  • Example 4 is a scanning electron micrograph of the glycine single crystal prepared in Example 10.
  • Fig. 5 is a scanning electron micrograph of raffinose single crystals prepared in Examples 11 and 12.
  • Example 6 is a scanning electron micrograph of glutathione single crystal prepared in Example 13.
  • Example 7 is a scanning electron micrograph of the erythromycin single crystal prepared in Example 14.
  • Example 10 is a scanning electron micrograph of the vitamin B 3 single crystal prepared in Example 19.
  • Example 11 is a scanning electron micrograph of a single crystal of lysozyme prepared in Example 20.
  • the lysozyme is derived from eggs.
  • Example 12 is a scanning electron micrograph of the alanine single crystal prepared in Example 21.
  • Example 13 is a scanning electron micrograph of the sodium chloride single crystal prepared in Example 22.
  • 15 is a scanning electron micrograph of the single crystal of penicillin G sodium salt prepared in Examples 26 and 27.
  • Example 16 is a scanning electron micrograph of carbenicillin disodium salt single crystal prepared in Example 28.
  • Example 17 is a scanning electron micrograph of the single crystal of nafcillin sodium monohydrate prepared in Example 29.
  • Fig. 20 is a scanning electron micrograph of ginsenoside Rd single crystals prepared in Examples 34 and 35.
  • Example 21 is a scanning electron micrograph of the gibberellin A 1 single crystal prepared in Example 36.
  • Example 22 is a scanning electron micrograph of the gibberellin A 5 single crystal prepared in Example 37.
  • Example 23 is a scanning electron micrograph and chemical structure formula of the AIE35 single crystal prepared in Example 38.
  • Example 24 is a scanning electron micrograph of rhodamine B single crystal prepared in Example 39.
  • Fig. 25 is a scanning electron micrograph of L-carnosine single crystals prepared in Examples 40, 41, and 42.
  • Fig. 26 is a scanning electron micrograph of the diglycine single crystal prepared in Example 43.
  • Example 29 is a scanning electron micrograph of the K 4 [Fe (CN) 6 ] single crystal prepared in Example 47.
  • FIG. 30 is a scanning electron micrograph of [Co (NH 3 ) 5 Cl] Cl 2 single crystal prepared in Example 48.
  • FIG. 30 is a scanning electron micrograph of [Co (NH 3 ) 5 Cl] Cl 2 single crystal prepared in Example 48.
  • Example 31 is a scanning electron micrograph and chemical structural formula of the C 6 H 9 NaO 7 single crystal prepared in Example 49.
  • Example 32 is a scanning electron micrograph of the malic acid single crystal prepared in Example 50.
  • Example 33 is a scanning electron micrograph of the sodium hydrogen phosphate single crystal prepared in Example 51.
  • Example 34 is a scanning electron micrograph of sodium sulfite single crystal prepared in Example 52.
  • Example 35 is a scanning electron micrograph of sodium benzoate single crystal prepared in Example 53.
  • Example 36 is a scanning electron micrograph of p-toluenesulfonic acid single crystal prepared in Example 54.
  • FIG. 37 is a schematic diagram of the principle of forming a single crystal according to the present invention.
  • Fig. 38 is a process diagram of the formation of a single crystal by AIE35 of the present invention.
  • Fig. 39 is a process diagram of forming single crystal of p-toluenesulfonic acid in the present invention.
  • the present invention provides a method for preparing a single crystal or an amorphous material using an aqueous solution.
  • the method includes the following steps:
  • step (a2) freezing the aqueous solution of the pseudo-crystalline substance in step (a1) and optionally aging to prepare a mixed system of single crystal or amorphous substance containing pseudo-crystalline substance and ice; optionally,
  • the present invention provides a method for preparing a single crystal, which includes the following steps:
  • step (a2) freezing the aqueous solution of the pseudo-crystalline substance in step (a1) and optionally aging to prepare a mixed system of single crystal and ice containing the pseudo-crystalline substance;
  • step (a3) Separate the mixed system of the single crystal of the pseudo-crystal substance and ice in step (a2) to prepare the single crystal of the pseudo-crystal substance;
  • the heating or cooling rate during the aging process is less than 10 ° C / min, and / or, the aging time during the aging process is at least 25 minutes.
  • the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min for a period of time to obtain a mixed system of single crystals and ice containing pseudo-crystalline substances.
  • the temperature is increased to a certain temperature at an arbitrary heating or cooling rate, and the aging is performed for at least 25 minutes to obtain a mixed system of single crystals and ice containing pseudo-crystalline substances.
  • the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min, and the aging is performed for at least 25 minutes to obtain a mixed system of single crystals and ice containing pseudo-crystalline substances.
  • the certain temperature reached is, for example, less than or equal to 0 ° C, and also, for example, less than or equal to -5 ° C; specifically, it may be -10 ° C, -15 ° C, -18 ° C, -20 ° C, -24 ° C, -25 ° C, -30 ° C, -72 ° C, -80 ° C, -90 ° C, -100 ° C or liquid nitrogen temperature, etc.
  • the temperature increase or decrease rate is less than 10 ° C / min, for example, may be less than 9 ° C / min, and further, for example, less than or equal to 5 ° C / min; depending on different pseudo-crystalline materials. It is not difficult to understand that if the speed is 0 ° C / min, it means that the temperature is maintained at the same temperature as the freezing temperature.
  • the aging time is at least 25 min, for example, it can be 30 min, 40 min, 50 min, 55 min, 60 min, 90 min, 100 min, 120 min, 150 min, 200 min, 300 min, 500 min or longer, etc .; according to different pseudo-crystallized substances It depends.
  • the present invention provides a method for preparing an amorphous substance, the method comprising the following steps:
  • step (a2) freezing and aging the aqueous solution of the pseudo-crystalline substance in step (a1) to prepare a mixed system of amorphous and ice containing pseudo-crystalline substance; optionally,
  • the heating or cooling rate during the aging process is greater than or equal to 10 ° C./min, and the aging time during the aging process is less than 25 min.
  • the temperature is cooked at a temperature of 10 °C / min or more to reach a certain temperature for less than 25 minutes, that is, an amorphous substance containing crystalline material and ice are obtained.
  • a temperature of 10 °C / min or more to reach a certain temperature for less than 25 minutes, that is, an amorphous substance containing crystalline material and ice are obtained.
  • the particle size of the obtained amorphous substance can be controlled by adjusting the temperature.
  • the certain temperature reached is, for example, less than or equal to 0 ° C, and also for example, less than or equal to -5 ° C; specifically, it may be -5 ° C, -7 ° C, -8 ° C, -10 ° C, -12 ° C, -20 °C, -45 °C, etc.
  • the temperature rises from the liquid nitrogen temperature to 10 ° C / min or more to the above temperature.
  • the temperature increase or decrease rate is greater than or equal to 10 ° C / min, for example greater than or equal to 15 ° C / min, for example, 15 ° C / min, 16 ° C / min, 17 ° C / min, 18 ° C / min, 19 ° C / min, 20 °C / min, 21 °C / min, 22 °C / min, 23 °C / min, 24 °C / min, 25 °C / min, 26 °C / min, 27 °C / min, 28 °C / min, 29 °C / min, 30 ° C / min or higher; the aging time is less than 25min, for example, can be less than 25min, less than or equal to 23min, less than or equal to 22min, less than or equal to 21min, less than or equal to 20min, less than or equal to 19min, less than or equal to 18min, less than or equal to 17min Or less than or equal to 16min
  • step (a1) the preparation of the aqueous solution of the quasi-crystalline substance may be performed using an operation method known to those skilled in the art, such as a preparation method using a standard solution.
  • the pseudo-crystalline substance includes but is not limited to inorganic and / or organic substances.
  • the pseudo-crystalline material includes but is not limited to inorganic substances and organic substances.
  • the inorganic substance is, for example, selected from metal salts or non-metal salts;
  • the organic substance is an organic molecule soluble in water, for example, selected from aromatic compounds, non-aromatic heterocyclic compounds, amino acids, sugars, polypeptides, proteins, Drugs, water-soluble metal organic complexes, etc.
  • the inorganic substance is selected from copper sulfate, sodium chloride, quaternary ammonium salt, etc .
  • the aromatic compound is selected from phenol, p-toluenesulfonic acid, naphthalenesulfonate formaldehyde condensate, etc.
  • the family hybrid compound is selected from purine compounds, for example; the metal organic complexes are, for example, water-soluble porphyrin metal complexes and the like.
  • the pseudo-crystalline substance has a certain solubility in water; those skilled in the art can understand that the solubility of the pseudo-crystalline substance in water can be arbitrary, that is, the pseudo-crystalline substance can be dissolved in water However, there is no particular limitation on the amount of water dissolved in it; it can be understood that the solubility of the quasi-crystalline substance in water may be, for example, easily soluble, soluble, slightly soluble or hardly soluble.
  • the amount of the pseudo-crystalline substance dissolved in water is greater than or equal to 1 ⁇ 10 -7 g / 100g, such as greater than or equal to 0.001g / 100g, such as greater than or equal to 0.01g / 100g, such as greater than Equal to 0.1g / 100g, such as greater than or equal to 1g / 100g, such as greater than or equal to 10g / 100g.
  • the concentration of the aqueous solution of the pseudo-crystalline substance is not particularly limited, that is, the pseudo-crystalline substance can be dissolved in water; as known to those skilled in the art, the pseudo-crystalline substance may be an unsaturated solution in water Or a saturated solution may also be a supersaturated solution; of course, the concentration of the aqueous solution of the pseudo-crystalline substance will have a great influence on the aggregation rate of the pseudo-crystalline substance.
  • the time required for single crystals or amorphous materials will increase correspondingly; when the concentration is higher, the pseudo-crystalline material aggregates faster, and the time required to obtain single crystals or amorphous materials will decrease accordingly.
  • the preparation time of the single crystal or amorphous material can be controlled by the solution concentration; of course, the preparation time of the single crystal or amorphous material is not only dependent on the concentration of the solution, which is related to the curing process (such as curing Temperature, curing time) are also closely related.
  • the concentration of the aqueous solution of the pseudo-crystalline substance is greater than or equal to 1 ⁇ 10 -7 g / 100g, such as greater than or equal to 0.001g / 100g, such as greater than or equal to 0.01g / 100g, such as greater than or equal to 0.1g / 100g, such as greater than or equal to 1g / 100g, such as greater than or equal to 10g / 100g.
  • the upper limit of the concentration of the aqueous solution of the pseudo-crystal substance is not particularly limited, and it may be a supersaturated solution or a saturated solution of the pseudo-crystal substance in water.
  • the concentration of the aqueous solution of the pseudo-crystalline substance is 1 ⁇ 10 ⁇ 7 g / 100 g to 1 g / 100 g.
  • the step (a2) specifically includes the following steps:
  • the aqueous solution of the pseudo-crystalline substance in step (a1) is cooled and frozen to a solid, and optionally subjected to aging treatment to prepare a mixed system of single crystal or amorphous substance containing pseudo-crystalline substance and ice.
  • the inventor unexpectedly discovered that during freezing of the aqueous solution, the water will freeze to a solid, and the pseudo-crystalline substance dissolved in the aqueous solution will achieve concentration aggregation at the ice interface, thereby forming a single crystal or Amorphous materials provide the possibility.
  • the grain size of a certain amount of ice will gradually become larger, and the pseudo-crystalline substance is gradually released from the disappeared solid solvent , So that the quasi-crystalline substance will continue to gather at the ice interface, form a single crystal or amorphous material and continue to grow or the formed single crystal or amorphous material will continue to grow, and finally the particle size of tens of nanometers to A single crystal of a quasi-crystalline substance of several hundred nanometers is shown in FIG. 36.
  • any wavelength cannot excite it to emit light, but when the molecule exists in an aggregated state, it will be excited by fluorescence; to prove that the ice crystals are freezing, or optionally further During the aging process, the solute molecules are gathered at the interface.
  • the aggregate luminescent material AIE35
  • the AIE35 aqueous solution is frozen into solid by any means, and ice will form separate polycrystalline systems. As shown in Figure 37, at the interface of any two ice crystals in contact, AIE35 forms aggregates, and crystallization. It can be seen from a in FIG.
  • test results show that the p-toluenesulfonic acid single crystal is formed during the freezing process, and the p-toluenesulfonic acid single crystal gradually grows during maturation, and the characteristic peak of p-toluenesulfonic acid is -1035cm -1
  • the generation of vibration) and the occurrence of blue shift also strongly prove that with maturation, the p-toluenesulfonic acid molecules continue to aggregate so that the formed single crystals continue to grow (see Figure 39).
  • the freezing includes but is not limited to complete freezing and incomplete freezing.
  • complete freezing means that the aqueous solution of the pseudo-crystalline substance in step (a1) is completely frozen into a solid
  • the incomplete freezing means that the aqueous solution of the pseudo-crystalline substance in step (a1) is partially frozen into Solid, partly still in liquid state.
  • the freezing may be any one or several methods of cooling the aqueous solution of the pseudo-crystalline substance having any volume and shape in any one One or several cooling processes will freeze it into a solid. That is, the freezing is to freeze the aqueous solution of the pseudo-crystalline substance in step (a1) to a solid or solid-liquid mixed state. Compared with the traditional evaporation method and cooling crystallization method, the freezing crystallization method has a larger control range for the concentration of the aqueous solution of the pseudo-crystal substance, and the time required to obtain the pseudo-crystal substance crystal is greatly shortened.
  • the freezing time, freezing temperature, freezing temperature gradient, freezing method, freezing process, etc. are not particularly limited, and an aqueous solution of a pseudo-crystalline substance of any volume and shape is frozen as a solid Or solid-liquid mixed state.
  • concentration of the pseudo-crystal substance aqueous solution can also be considered to make a reasonable choice, the purpose is to control the diffusion rate of water molecules and pseudo-crystal substance molecules, thereby affecting the crystallization process.
  • the freezing time selected at this time can be appropriately shortened and the freezing temperature can be appropriately reduced; the purpose of this operation is to prevent the quasi-crystalline substance in the solution of higher concentration from being difficult to control If the concentration of the aqueous solution of the pseudo-crystalline substance is low, the freezing time selected at this time can be appropriately extended and the freezing temperature can be appropriately increased; the purpose of this operation is to achieve the effective aggregation of the pseudo-crystalline substance molecules, and then form no Stereotypes or single crystals.
  • the freezing method is an operation method known to those skilled in the art, for example, using any refrigeration device for cooling and freezing or using any low-temperature substance for cooling and freezing; exemplarily, the frozen Methods include but are not limited to compression refrigeration equipment cooling freezing, semiconductor refrigeration equipment cooling freezing, liquid nitrogen cooling freezing, liquid helium cooling freezing, liquid carbon dioxide cooling freezing, liquid oxygen cooling freezing, liquid ethane cooling freezing, dry ice cooling freezing, ice cooling freezing One or a combination of several cooling methods.
  • the operating pressure of the freezing is also not limited, and it may be freezing under normal pressure, or freezing treatment under high pressure or low pressure.
  • the freezing process is an operation method known to those skilled in the art.
  • the aqueous solution of the quasi-crystalline substance is frozen from a liquid state to a solid state by any process.
  • the freezing process includes but It is not limited to one or a combination of several freezing processes in rapid cooling, slow cooling, step cooling, first heating and then cooling.
  • the volume and shape of the aqueous solution of pseudo-crystalline substance are not particularly limited; the volume and shape of the solid frozen from the aqueous solution of pseudo-crystalline substance are also not particularly limited, as long as it can be frozen to obtain a solid or solid-liquid The mixed state may be sufficient; those skilled in the art can understand that the freezing may be to freeze the aqueous solution of the pseudo-crystal substance in any volume as a whole, or to freeze the film formed by the aqueous solution of the pseudo-crystal substance in any volume, or Freeze droplets formed from any volume of pseudo-crystalline substance aqueous solution.
  • the crystallization method may optionally be ripened, and the ripening process may be used to form a single crystal of a system that does not form a single crystal during the freezing process, control the growth speed of the single crystal, and control the size of the single crystal; also It can be used to further optimize the control of the growth rate of the single crystal and the size of the single crystal in the system where the single crystal is formed during the freezing process. Since the aging process is not limited by temperature, it can also reduce the energy consumption due to the low temperature required in the freezing process, reduce costs, and provide convenience for industrial production.
  • the quasi-crystalline substance aqueous solution frozen into a solid is subjected to aging treatment; the aging temperature, aging time, and aging process in the aging treatment process are not particularly limited, but the aging treatment needs to be ensured
  • the aqueous solution of the pseudo-crystalline substance frozen into a solid during the process may remain in a solid state, that is, the aqueous solution of the pseudo-crystalline substance during the ripening process remains frozen; for example, the solid is cured in the same way as the freezing process, or Other methods are used to ripen the solid; the purpose of the ripening treatment is to realize the adjustment of the aggregation of the pseudo-crystalline substance and the growth speed of the nanoparticles, and then to prepare the single crystal or the amorphous substance of the pseudo-crystalline substance.
  • the curing temperature should be lower than the temperature at which the frozen aqueous solution of the pseudo-crystalline substance is melted again (ie, T melting ).
  • T melting the temperature at which the frozen aqueous solution of the pseudo-crystalline substance is melted again.
  • the curing temperature is lower than T melting by 5 ° C or more, more preferably Lower than T melting above 10 °C.
  • the aging process is that the aqueous solution of the quasi-crystalline substance stays in a frozen state for a period of time.
  • the frozen state here may be completely frozen or incompletely frozen, and it may be selected according to operations known to those skilled in the art.
  • the aging process uses, for example, rapid temperature increase (or temperature decrease) or slow temperature increase (or temperature decrease).
  • the temperature increase or decrease rate of the aging process is greater than or equal to 10 ° C / min, This range of heating or cooling rate will quickly release solute molecules from the solid mixture and produce disordered aggregation. By limiting the aging time, it provides a guarantee for the preparation of amorphous materials.
  • the heating or cooling rate of the aging process is less than 10 ° C./min, and the heating or cooling rate in this range will slowly release solute molecules from the solid mixture to produce ordered aggregation, and a single crystal can be prepared.
  • the curing temperature controls the size of the ice particles and the aggregation rate of the pseudo-crystalline material, that is, the greater the temperature difference between the curing temperature and the freezing temperature, the larger the size of the ice particles .
  • the quasi-crystalline material aggregates faster, and the time required to form a single crystal or amorphous material is shorter, then the particle size of the prepared single crystal or amorphous material is also larger; the temperature difference between the curing temperature and the freezing temperature
  • the aging time there is no particular limitation on the aging time, which can be performed by operations known to those skilled in the art.
  • the aging process It can be understood as the process of nucleation and growth of amorphous materials or the formation and growth of single crystals.
  • Properly extending the curing time can obtain single crystals or amorphous materials with complete particle size and morphology, but it should be noted that due to the adjustment
  • the essence of the curing time is to adjust the aggregation concentration of the quasi-crystalline substance. Prolonged aging may cause the aggregation concentration to be too high, which is not conducive to the formation of amorphous or single crystal.
  • the aging time is greater than 1 picosecond, preferably, the aging time is 1 to 1000 minutes, and further preferably, the aging time is 10 to 300 minutes.
  • the aging time is less than 25 minutes, and by adjusting the temperature increase or decrease rate in the aging process, the preparation of the amorphous material can be achieved.
  • the aging time is greater than or equal to 25 min, the aggregation concentration of the quasi-crystalline substance can be further adjusted, for example, a single crystal can be prepared.
  • the aging time should not be too long. The excessively long aging time may make the obtained single crystal further into a polycrystalline structure.
  • the aging process may be any refrigeration device or any low temperature, so that the aqueous solution of the crystalline substance remains frozen; for example, compression refrigeration equipment, semiconductor refrigeration equipment, or liquid nitrogen or liquid helium , Liquid carbon dioxide, liquid oxygen, liquid ethane, dry ice, ice, etc. one or a combination of several methods.
  • the separation of the ice may use physical and / or chemical methods to separate the ice.
  • the single crystal or amorphous material has been prepared after freezing or optional further aging. At this time, the single crystal or amorphous material exists at the ice interface, and it needs to be separated by an appropriate method; or the ice is removed .
  • the physical means include but are not limited to one or a combination of mechanical separation and sublimation (such as vacuum sublimation).
  • the sublimation may be performed by freeze drying, for example; the vacuum sublimation may be performed by freeze drying under vacuum conditions, for example.
  • the chemical means include, but are not limited to, one or a combination of chemical reactions and electrolysis.
  • the method further includes the following steps:
  • step (a4) The single crystal or amorphous prepared in step (a3).
  • the collection includes but is not limited to one or a combination of optical microscope collection, scanning electron microscope collection, dual-beam electron microscope collection, and transmission electron microscope collection .
  • the present invention also provides a method for cultivating a single crystal, which includes the above-mentioned method for preparing a single crystal.
  • the method for cultivating a single crystal further includes the following steps:
  • step (b2) Collect the single crystal of step (b1).
  • the transfer is any method known to those skilled in the art that can transfer single crystals, including but not limited to optical microscope transfer, scanning electron microscope transfer, and dual-beam electron microscope transfer , One or a combination of several in the transmission electron microscope.
  • the mother liquor is a mother liquor system known to those skilled in the art that is compatible with the single crystal to be cultured.
  • the aging time described in the following examples refers to the time required to raise or lower the temperature to the aging temperature after the freezing process ends, and the time maintained at the aging temperature; the maintenance time refers to the maintenance at the aging temperature time.
  • benzyl penicillin solution with a concentration of 10 mM in ultrapure water, take a 15 ⁇ L solution with a pipette and drop it onto a silicon wafer at -90 ° C.
  • the temperature of the silicon wafer is controlled by a hot and cold stage, and then at 5 ° C / min The rate of temperature rise to -25 °C, maintained at this temperature for 60min.
  • freeze-dry the sample completely sublimate the solid ice, and then select a single crystal of better quality from the silicon wafer to a saturated benzyl penicillin solution and place it in a constant temperature and humidity environment with a temperature of 25 ° C and a relative humidity of 40%. In time, you can grow larger benzyl penicillin crystals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Materials Engineering (AREA)
  • Metallurgy (AREA)
  • Organic Chemistry (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)

Abstract

一种利用水溶液制备单晶或无定型物的方法，该方法适用于任何水溶性分子单晶或无定型物的制备与培养。包括以下步骤：(a1)配制拟结晶物质的水溶液；(a2)对步骤(a1)的拟结晶物质的水溶液进行冻结，任选地进行熟化，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系；任选地，(a3)分离步骤(a2)的拟结晶物质的单晶或无定型物和冰的混合体系，得到拟结晶物质的单晶或无定型物。该方法针对传统方法培养单晶或无定型物过程中分子成核及聚集速度难以控制等缺陷，首次提出了以水溶液冻结诱导溶质分子的成核与结晶，快速有效地制备溶质分子单晶或无定型物。

Description

一种利用水溶液制备单晶或无定型物的方法
本申请要求2018年10月30日向中国国家知识产权局提交的专利申请号为2018112792527，发明名称为“一种利用水溶液制备与培养单晶的方法”在先申请的优先权，该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及单晶或无定型物的制备领域，具体涉及一种利用水溶液制备单晶或无定型物的方法，该方法适用于任何水溶性分子单晶或无定型物的制备。
技术背景
单晶在现代各种科学领域具有举足轻重的地位，例如有机分子及蛋白质结构分析，光电器件，医药以及航空航天等领域。目前分子结晶的方法被广泛的研究，常用的有溶剂缓慢挥发法、降温法、液相扩散法、高分子诱导结晶和气相扩散法等。但是上述方法普遍存在晶体成核与生长可控性差、单晶生长困难、容易产生多晶等问题。有些分子甚至无法采用上述方法获得单晶，因此如何高效制备完美单晶依旧是一项巨大的挑战。此外，某些无定型物在科学领域也扮演着重要角色。
发明内容
为了解决现有技术中存在的问题，本发明提供一种利用水溶液制备单晶或无定型物的方法。
一种利用水溶液制备单晶或无定型物的方法，所述方法包括以下步骤：
(a1)配制拟结晶物质的水溶液；
(a2)对步骤(a1)的拟结晶物质的水溶液进行冻结；
任选地进行熟化，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系；
任选地，(a3)分离步骤(a2)的拟结晶物质的单晶或无定型物和冰的混合体系，得到拟结晶物质的单晶或无定型物。
根据本发明，步骤(a1)中
所述水包括但不限于超纯水、二次水、去离子水。
所述拟结晶物质包括但不限于无机物和/或有机物。
所述拟结晶物质在水中的溶解度为难溶、微溶、可溶或易溶。
本发明中，所述步骤(a2)具体包括如下步骤：
将步骤(a1)的拟结晶物质的水溶液降温冻结成固体混合物，并任选地进行熟化处理，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系。
本发明中，在步骤(a2)中，所述冻结是将步骤(a1)的拟结晶物质的水溶液由液态转化为固态。
本发明中，所述冻结的方法包括但不限于压缩制冷设备降温冻结、半导体制冷设备降温冻结、液氮降温冻结、液氦降温冻结、液态二氧化碳降温冻结、液态氧降温冻结、液态乙烷降温冻结、干冰降温冻结、冰降温冻结等中的一种或几种降温冻结方法的组合。
本发明中，所述冻结的过程包括但不限于快速降温、缓慢降温、分步降温、先升温后降温等中的一种或者几种冻结过程的组合。
本发明中，所述冻结包括但不限于完全冻结，未完全冻结。
本发明中，所述熟化即维持拟结晶物质的水溶液仍保持冻结状态一段时间。
本发明中，所述的熟化时间是指冻结过程结束后，升温或降温至熟化温度所需的时间，以及在熟化温度下维持的时间。
在一个实施方式中，所述步骤(a2)，对步骤(a1)的拟结晶物质的溶液进行冻结，制备得到含有拟结晶物质的单晶和冰的混合体系。
在一个实施方式中，所述步骤(a2)中包括熟化处理步骤，即所述步骤(a2)中，对步骤(a1)的拟结晶物质的溶液进行冻结和熟化处理，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系。
在一个实施方式中，所述步骤(a2)，在熟化过程中，将温度以大于或等于10℃/min的升温或降温速度达到某一温度，且所述熟化的时间小于25min，制备得到含有拟结晶物质的无定型物和冰的混合体系。
又一个实施方式中，所述达到的某一温度与冻结温度之间的差异越大，所得到的无定型物的颗粒尺寸越大。因此可以通过调整该温差的大小来控制所获得的无定型物的颗粒尺寸。
在一个实施方式中，所述步骤(a2)，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，和/或所述熟化的时间至少为25min，制备得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，保持一段时间，制备得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，在熟化过程中，将温度以任意升温或降温速度达到某一温度，熟化至少25min，制备得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，熟化至少25min，制备得到含有拟结晶物质的单晶和冰的混合体系。
本发明中，在步骤(a3)中，所述分离采用物理方式和/或化学方式将单晶与冰进行分离。
本发明中，所述的物理方式包括但不限于机械分离、升华(如真空升华)中的一种或几种方式的组合。
本发明中，所述的化学方式包括但不限于化学反应、电解中的一种或几种方式的组合。
本发明中，所述方法还包括如下步骤：
(a4)收集步骤(a3)制备得到的单晶或无定型物。
本发明中，在步骤(a4)中，所述收集包括但不限于采用光学显微镜收集、扫描电子显微镜收集、双束电子显微镜收集、透射电子显微镜收集中的一种或几种的组合。
本发明还提供一种培养单晶的方法，所述方法包括上述的制备单晶的方法。
本发明中，所述培养单晶的方法还包括如下步骤：
(b1)将上述制备的拟结晶物质的单晶转移到拟结晶物质的母液中进行培养；
(b2)对步骤(b1)培养的单晶进行收集。
在步骤(b1)中，所述的转移可以是将步骤(a2)的含有拟结晶物质的单晶和冰的混合体系转移到拟结晶物质的母液中进行单晶培养；或者是将步骤(a3)的去除冰后的单晶直接转移到拟结晶物质的母液中进行单晶培养；或者是将步骤(a4)收集到的单晶转移到拟结晶物质的母液中进行单晶培养。
本发明中，所述的转移包括但不限于光学显微镜移取、扫描电子显微镜移取、双束电子显微镜移取、透射电子显微镜移取中的一种或几种的组合。
本发明中，在步骤(b1)中，所述单晶的培养方法包括但不限于蒸发法、降温法、扩散法中的一种或几种的组合。
本发明中，在步骤(b2)中，所述收集包括但不限于采用光学显微镜收集、扫描电子显微镜收集、双束电子显微镜收集、透射电子显微镜收集中的一种或几种的组合。
有益效果
(1)针对传统方法制备单晶或无定型物过程中分子供给、聚集及成核速度难以控制等缺陷，本发明首次提出以控制水溶液冻结诱导溶质分子的成核与结晶的方法。在水结晶过程中实现所溶解的溶质分子的结晶，利用调控水溶液的冻结，和任选地熟化过程，快速有效地制备溶质分子单晶或无定型物。同时，解决传统单晶制备与培养过程中难以结晶分子的单晶制备问题，还可以解决一些物质较难形成无定型物，特别是形成高纯度的无定型物的问题，具有普适性。
(2)本发明在研究过程中发现，相比于传统蒸发法或降温结晶法，本发明采用冰重结晶方法，溶液浓度调控范围更大，从很低浓度到过饱和浓度均可实现单晶或无定型物的制备。首次实现了在极低溶液浓度下单晶或无定型物的获取；还解决了高浓度下由于溶质分子的聚集过快而导致的单晶形成不易控制、易形成多晶和/或孪晶等问题；另外，本发明还具有在很短时间(几分钟到数小时)内得到拟结晶物质单晶或无定型物的特点。
(3)本发明中溶液冻结为一技术关键点。所述冻结过程是指使水溶液以任意的方式冻结，冻结的时间、冻结的温度、冻结的温度梯度、冻结的方法、冻结的过程等均没有特别的限定。实验证实，通过水溶液冻结制备溶质单晶或无定型物的本质在于，在冻结的过程中，水分子形成冰晶的同时，溶质分子会被释放并聚集在冰晶界面处，通过控制对水冻结过程以及冰晶的重结晶的调控，从而进一步调控其中溶质分子的释放和聚集速率，有效地实现对于溶质分子的成核及生长的调控，进而获取目标分子的单晶或无定型物。
(4)本发明所述熟化过程是指使冻结的水溶液在固体状态下保持一定的时间，温度不受限定，但是升温或降温速度需要控制。实验证实，本发明所述的熟化过程任选地作为冻结过程的补充手段，能够优化对于冰晶重结晶过程的调控，从而调控冰晶中溶质分子的释放速率以及溶质分子向冰晶界面处的聚集速率，有利于进一步优化溶液冻结后无定型物的生长和单晶的成核、生长。不仅如此，熟化过程由于对温度没有过多的限定，冻结后的体系无需继续冻结而是经过熟化过程就可以获得颗粒尺寸在纳米至微米范围内的单晶或无定型物，从而有利于选择在更经济的温度下，以更高的效率实现单晶或无定型物的优化制备，有利于能耗的降低从而极大节省成本。与传统方法相比，本发明通过调控熟化过程中的升温或降温速率实现对冰晶重结晶进行优化调控，可进一步调控冰晶中溶质分子向冰晶界面处的聚集速度，进而有效地得到溶质分子的单晶或无定型物，其具有节约能源、提高效率等优势，更有利于大规模工业化生产。
(5)本发明提供的单晶或无定型物的制备方法和进一步的培养方法的适用范围广，对于现有的无机物和有机物均适用，此外，还可利用该方法实现传统方法难以结晶的物质的单晶或无定型物获取。且实验方法简单，操作性强。本发明所述方法不仅在实验室基础研究中适用，同样满足在工业生产的需求。
附图说明
图1为实施例1,2,3制备的硫酸铜单晶的扫描电镜照片。
图2为实施例4,7,8,9制备的谷氨酸单晶的扫描电镜照片。
图3为实施例5,6制备的苄基青霉素单晶的扫描电镜照片。
图4为实施例10制备的甘氨酸单晶的扫描电镜照片。
图5为实施例11,12制备的棉子糖单晶的扫描电镜照片。
图6为实施例13制备的谷胱甘肽单晶的扫描电镜照片。
图7为实施例14制备的红霉素单晶的扫描电镜照片。
图8为实施例15,16制备的海藻糖单晶的扫描电镜照片。
图9为实施例17,18制备的酒石酸单晶的扫描电镜照片。
图10为实施例19制备的维生素B 3单晶的扫描电镜照片。
图11为实施例20制备的溶菌酶的单晶的扫描电镜照片，溶菌酶来源于鸡蛋。
图12为实施例21制备的丙氨酸单晶的扫描电镜照片。
图13为实施例22制备的氯化钠单晶的扫描电镜照片。
图14为实施例23,24,25制备的氯霉素单晶的扫描电镜照片。
图15为实施例26,27制备的青霉素G钠盐单晶的扫描电镜照片。
图16为实施例28制备的羧苄青霉素二钠盐单晶的扫描电镜照片。
图17为实施例29制备的萘夫西林钠单水合物单晶的扫描电镜照片。
图18为实施例30,31制备的人参皂苷Rh 2单晶的扫描电镜照片。
图19为实施例32,33制备的人参皂苷Rb 2单晶的扫描电镜照片。
图20为实施例34,35制备的人参皂苷Rd单晶的扫描电镜照片。
图21为实施例36制备的赤霉素A 1单晶的扫描电镜照片。
图22为实施例37制备的赤霉素A 5单晶的扫描电镜照片。
图23为实施例38制备的AIE35单晶的扫描电镜照片及化学结构式。
图24为实施例39制备的若丹明B单晶的扫描电镜照片。
图25为实施例40,41,42制备的L-肌肽单晶的扫描电镜照片。
图26为实施例43制备的双甘肽单晶的扫描电镜照片。
图27为实施例44制备的氨肽酶单晶的扫描电镜照片。
图28为实施例45,46制备的[Cu(NH 3) 4]SO 4单晶的扫描电镜照片。
图29为实施例47制备的K 4[Fe(CN) 6]单晶的扫描电镜照片。
图30为实施例48制备的[Co(NH 3) 5Cl]Cl 2单晶的扫描电镜照片。
图31为实施例49制备的C 6H 9NaO 7的单晶的扫描电镜照片及化学结构式。
图32为实施例50制备的苹果酸单晶的扫描电镜照片。
图33为实施例51制备的磷酸氢钠单晶的扫描电镜照片。
图34为实施例52制备的亚硫酸钠单晶的扫描电镜照片。
图35为实施例53制备的苯甲酸钠单晶的扫描电镜照片。
图36为实施例54制备的对甲基苯磺酸单晶的扫描电镜照片。
图37为本发明形成单晶的原理示意图。
图38为本发明AIE35形成单晶的过程图。
图39为本发明对甲基苯磺酸形成单晶的过程图。
具体实施方式
本发明中，“任选地”表示进行或者不进行后续步骤。
[制备单晶或无定型物的方法]
如前所述，本发明提供一种利用水溶液制备单晶或无定型物的方法，所述方法包括如下步骤：
(a1)配制拟结晶物质的水溶液；
(a2)对步骤(a1)拟结晶物质的水溶液进行冻结，任选地熟化，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系；任选地，
(a3)从步骤(a2)的含有拟结晶物质的单晶或无定型物和冰的混合体系中分离得到拟结晶物质的单晶或无定型物。
[制备单晶的方法]
如前所述，本发明提供一种制备单晶的方法，所述方法包括如下步骤：
(a1)配制拟结晶物质的水溶液；
(a2)对步骤(a1)的拟结晶物质的水溶液进行冻结，任选地熟化，制备得到含有拟结晶物质的单晶和冰的混合体系；
(a3)分离步骤(a2)的拟结晶物质的单晶和冰的混合体系，制备得到拟结晶物质的单晶；
其中，所述熟化的过程中升温或降温速率小于10℃/min，和/或，所述熟化的过程中熟化的时间至少为25min。
示例性地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，保持一段时间，即得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，在熟化过程中，将温度以任意升温或降温速度达到某一温度，熟化至少25min，即得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，熟化至少25min，即得到含有拟结晶物质的单晶和冰的混合体系。
示例性地，所述达到的某一温度例如小于等于0℃，还例如小于等于-5℃；具体的，可以是-10℃、-15℃、-18℃、-20℃、-24℃、-25℃、-30℃、-72℃、-80℃、-90℃、-100℃或液氮温度，等等。
如上所述，所述升温或降温速率小于10℃/min，例如可以是小于9℃/min，进一步例如小于等于5℃/min；根据不同的拟结晶物质而定。不难理解，若速度为0℃/min，则表示维持与冻结温度一样的温度熟化。
如上所述，所述熟化时间至少为25min，例如可以为30min、40min、50min、55min、60min、90min、100min、120min、150min、200min、300min、500min或更长等等；根据不同的拟结晶物质而定。
[制备无定型物的方法]
如前所述，本发明提供一种制备无定型物的方法，所述方法包括如下步骤：
(a1)配制拟结晶物质的水溶液；
(a2)对步骤(a1)的拟结晶物质的水溶液进行冻结，熟化，制备得到含有拟结晶物质的无定型和冰的混合体系；任选地，
(a3)从步骤(a2)的混合体系中分离得到拟结晶物质的无定型；
其中，所述熟化的过程中升温或降温速率大于等于10℃/min，所述熟化的过程中熟化的时间小于25min。
示例性地，所述步骤(a2)的熟化过程中，将温度以大于等于10℃/min的升温或降温速度达到某一温度熟化小于25min，即得到含有拟结晶物质的无定型物和冰的混合体系。
在一个实施方式中，所述达到的某一温度与冻结温度之间的差异越大，所得到的无定型物的颗粒尺寸越大。因此可以通过调整该温度的高低来控制所获得的无定型物的颗粒尺寸。示例性地，所述达到的某一温度例如小于等于0℃，还例如小于等于-5℃；具体的，可以是-5℃、-7℃、-8℃、-10℃、-12℃、-20℃、-45℃，等等。优选地，自液氮温度以大于等于10℃/min的升温速度上升到上述温度。
如上所述，所述升温或降温速率大于等于10℃/min，例如大于等于15℃/min，例如可以是15℃/min、16℃/min、17℃/min、18℃/min、19℃/min、20℃/min、21℃/min、22℃/min、23℃/min、24℃/min、25℃/min、26℃/min、27℃/min、28℃/min、29℃/min、30℃/min或更高；所述熟化时间小于25min，例如可以小于25min、小于等于23min、小于等于22min、小于等于21min、小于等于20min，小于等于19min、小于等于18min、小于等于17min或小于等于16min等；根据不同的拟结晶物质而定。
[上述方法中的具体方案]
根据本发明的实施方案，在步骤(a1)中，所述拟结晶物质的水溶液的配制采用本领域技术人员已知的操作方式进行即可，如采用标准溶液的配制方法。
根据本发明的实施方案，所述拟结晶物质包括但不限于无机物和/或有机物。所述拟结晶物质包括但 不限于无机物和有机物。所述无机物例如选自金属盐或非金属盐等；所述有机物为可溶解在水中的有机分子，例如选自芳香族化合物、非芳香族杂环化合物、氨基酸、糖类、多肽、蛋白质、药物、水溶性金属有机配合物等等。例如所述无机物例如选自硫酸铜，氯化钠，季铵盐等；所述芳香族化合物例如选自苯酚，对甲基苯磺酸，萘磺酸盐甲醛缩合物等，所述非芳香族杂化化合物例如选自嘌呤类化合物；所述金属有机配合物例如水溶性双卟啉金属配合物等。
根据本发明的实施方案，所述拟结晶物质在水中具有一定的溶解度；本领域技术人员可以理解，所述拟结晶物质在水中的溶解度可以为任意的，即拟结晶物质可以溶解在水中即可，而对其溶解在水中的量没有特别的限定；可以理解，所述拟结晶物质在水中的溶解度例如可以为易溶、可溶、微溶或难溶。
根据本发明的实施方案，优选地，所述拟结晶物质在水中溶解的量为大于等于1×10 -7g/100g，例如大于等于0.001g/100g，如大于等于0.01g/100g，如大于等于0.1g/100g，如大于等于1g/100g，如大于等于10g/100g。
根据本发明的实施方案，所述拟结晶物质水溶液的浓度没有特别的限定，即拟结晶物质能够溶解在水中即可；本领域技术人员知晓的，所述拟结晶物质在水中可以为非饱和溶液或饱和溶液，也可以为过饱和溶液；当然，所述拟结晶物质水溶液的浓度的高低对于拟结晶物质的聚集速率会有很大影响，浓度较低时，拟结晶物质聚集速度较慢，获取单晶或无定型物所需时间会相应增加；浓度较高时，拟结晶物质聚集速度较快，获取单晶或无定型物所需时间会相应减少。因此，通过合理的选择浓度，实现通过溶液浓度调控单晶或无定型物的制备时间；当然制备单晶或无定型物的时间不仅仅只取决于溶液的浓度，这与熟化处理过程(例如熟化温度、熟化时间)也有紧密的联系。
根据本发明的实施方案，所述拟结晶物质的水溶液的浓度为大于等于1×10 -7g/100g，例如大于等于0.001g/100g，如大于等于0.01g/100g，如大于等于0.1g/100g，如大于等于1g/100g，如大于等于10g/100g。所述拟结晶物质的水溶液的浓度的上限没有特别的限定，其可以为拟结晶物质在水中的过饱和溶液或饱和溶液。
优选地，所述拟结晶物质的水溶液的浓度为1×10 -7g/100g到1g/100g。
根据本发明，所述步骤(a2)具体包括如下步骤：
将步骤(a1)的拟结晶物质的水溶液降温冻结成固体，并任选地进行熟化处理，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系。
根据本发明的实施方案，发明人出人意料地发现了所述水溶液在冻结过程中，水会冻结为固体，而溶解于水溶液中的拟结晶物质会在冰界面处实现浓度聚集，进而形成单晶或无定型物提供了可能。另外，冻结的拟结晶物质的水溶液，当进一步处于冻结过程和任选地进一步的熟化过程时，一定数量的冰的晶粒尺寸会逐渐变大，拟结晶物质逐步从消失的固体溶剂中释放出来，从而拟结晶物质会在冰的界面处不断聚集，形成单晶或无定型物并不断长大或已形成的单晶或无定型物会不断长大，最后可以获得颗粒尺寸在几十纳米至几百纳米的拟结晶物质的单晶，如图36所示。示例性地，聚集发光材料在游离的分子状态时，任意的波长均不能激发使其发光，但该分子以聚集态存在时，会被激发出荧光；为证明冰晶在冻结、或任选地进一步熟化过程中将溶质分子聚集在其界面处，我们选择了聚集发光材料(AIE35)验证了该过程。实验过程中，AIE35水溶液通过任一种方式冻结成固体，冰会形成分别独立存在的多晶体系，如图37所示，在任两个相接触的冰晶体界面处，AIE35均形成聚集体，进而结晶。由图38中a可知，界面处的荧光增强，说明AIE35分子可以在界面处聚集且逐步从无定型态物质过渡形成AIE35纳米单晶。并且由图38中b可知，界面处形成的聚集体经历了从无定型态到单晶的转换，并且，其单晶的体积逐渐增大。其中图38为透射电镜和电子衍射表征结果。
为了进一步证明单晶形成的原理，我们采用对甲基苯磺酸分子，采用透射电镜原位低温衰减全反射红外，观察对甲基苯磺酸在水的冻结、熟化过程中的聚集并形成单晶、单晶不断长大的过程。检测结果表 明，冻结过程形成对甲基苯磺酸单晶，该对甲基苯磺酸单晶在熟化时逐渐生长，同时对甲基苯磺酸的特征峰-1035cm -1(磺酸根的伸缩振动)的产生并发生蓝移也再次有力地证明随着熟化，对甲基苯磺酸分子不断聚集使得形成的单晶不断长大(见图39)。
根据本发明的实施方案，在步骤(a2)中，所述的冻结包括但不限于完全冻结，未完全冻结。本领域技术人员可以理解，所述完全冻结是指步骤(a1)的拟结晶物质的水溶液被完全冻结成固体；所述未完全冻结是指步骤(a1)的拟结晶物质的水溶液部分被冻结成固体，部分还为液体状态。
根据本发明的实施方案，在步骤(a2)中，本领域技术人员可以理解，所述冻结可以是以任意一种或几种降温方法对具有任意体积和形状的拟结晶物质的水溶液以任意一种或几种降温过程将其冻结为固体。即所述冻结是将步骤(a1)的拟结晶物质的水溶液冻结为固体或固液混合态。所述冻结结晶法相比于传统的蒸发法和降温结晶法，对拟结晶物质的水溶液浓度调控范围更大，得到拟结晶物质晶体所需时间极大缩短。
根据本发明的实施方案，所述冻结的时间、冻结的温度、冻结的温度梯度、冻结的方法、冻结的过程等均没有特别的限定，将任意体积和形状的拟结晶物质的水溶液冻结为固体或固液混合态即可。当然，在冻结过程中也可以考量拟结晶物质水溶液的浓度进行合理的选择，目的是为了控制水分子和拟结晶物质分子的扩散速率，进而影响其结晶过程。示例性地，若拟结晶物质水溶液的浓度较高时，此时选用的冻结时间可以适当缩短、冻结温度可以适当降低；这样操作的目的是为了防止较高浓度的溶液中的拟结晶物质难以控制地形成多晶；若拟结晶物质水溶液的浓度较低时，此时选用的冻结时间可以适当延长、冻结温度可以适当提高；这样的操作的目的是实现拟结晶物质分子有效的聚集，进而形成无定型物或单晶。
根据本发明的实施方案，所述冻结的方法为本领域技术人员已知的操作方式，例如采用任意制冷装置进行降温冻结操作或是采用任意低温物质进行降温冻结；示例性地，所述冻结的方法包括但不限于压缩制冷设备降温冻结、半导体制冷设备降温冻结、液氮降温冻结、液氦降温冻结、液态二氧化碳降温冻结、液态氧降温冻结、液态乙烷降温冻结、干冰降温冻结、冰降温冻结等中的一种或几种降温冻结方法的组合。
根据本发明的实施方案，所述冻结的操作压力同样没有限定，其可以为常压下的冻结，也可以为高压或低压下的冻结处理。
根据本发明的实施方案，所述冻结的过程为本领域技术人员已知的操作方式，例如通过任意过程使拟结晶物质的水溶液由液态冻结为固态，示例性地，所述冻结的过程包括但不限于快速降温、缓慢降温、分步降温、先升温后降温等中的一种或者几种冻结过程的组合。
根据本发明的实施方案，所述拟结晶物质水溶液的体积和形状没有特别的限定；拟结晶物质水溶液冻结成的固体的体积与形状同样没有特别的限定，只要能将其冷冻得到固体或固液混合态即可；本领域技术人员可以理解的，所述冻结可以是将任意体积的拟结晶物质的水溶液进行整体冻结、或者是将任意体积的拟结晶物质水溶液形成的膜进行冻结、又或者是将任意体积的拟结晶物质水溶液形成的液滴进行冻结。
根据本发明的实施方案，所述结晶方法可以任选进行熟化，熟化过程可以用于冻结过程未形成单晶的体系的单晶的形成、控制单晶生长的速度以及控制单晶的大小；也可以用于进一步优化冻结过程形成单晶的体系的单晶的生长速度的控制以及单晶大小的控制。由于熟化过程不受温度限制，这还可以降低由于冻结过程中所需的低温而产生的能耗、降低成本，为工业化生产提供方便。
根据本发明的实施方案，对冻结成固体的拟结晶物质水溶液进行熟化处理；所述熟化处理过程中熟化的温度、熟化的时间、熟化的过程均没有特别的限定，但需保证所述熟化处理过程中冻结成固体的拟结晶物质的水溶液仍保持固体状态即可，即所述熟化过程中拟结晶物质水溶液仍保持冻结状态；例如采用与冻结处理相同的方法对所述固体进行熟化处理，或采用其他的方法对所述固体进行熟化；所述熟化处理的目的是为了实现拟结晶物质聚集与纳米颗粒生长生长速度的调控，进而制备得到拟结晶物质的单晶或无定型物。本领域技术人员能够理解，所述熟化温度应为低于使已冻结的拟结晶物质的水溶液重新融化的温度(即T 融化)，优选的所述熟化温度低于T 融化5℃以上，更优选低于T 融化10℃以上。
根据本发明的实施方案，所述熟化过程即为拟结晶物质的水溶液在保持冻结状态下停留一段时间。这里的冻结状态可以为完全冻结，也可以为未完全冻结，根据本领域技术人员已知的操作进行选择即可。
根据本发明的实施方案，所述熟化过程，例如采用快速升温(或降温)或缓慢升温(或降温)等方式，示例性地，所述熟化过程的升温或降温速率大于等于10℃/min，此范围的升温或降温速率会使溶质分子从固体混合物中快速释放并且产生无序聚集，通过对熟化时间的限定，为制备得到无定型物提供保障。
示例性地，所述熟化过程的升温或降温速率小于10℃/min，此范围的升温或降温速率会使溶质分子从固体混合物中缓慢释放进而产生有序聚集，可以制备得到单晶。
根据本发明的实施方案，熟化温度(即所述达到的某一温度)控制的是冰粒的尺寸大小以及拟结晶物质聚集速度，即熟化温度与冻结温度的温差越大，冰粒尺寸较大，拟结晶物质聚集速度较快，形成单晶或无定型物所需时间较短，那么制备得到的拟结晶物质的单晶或无定型物的颗粒尺寸也较大；熟化温度与冻结温度的温差越小，冰粒尺寸较小，拟结晶物质聚集速度较慢，形成单晶或无定型物所需时间较长，且制备得到的拟结晶物质的单晶或无定型物的颗粒尺寸也较小。即熟化温度与冻结温度的温差越大，制备得到拟结晶物质的单晶或无定型物的颗粒尺寸也较大。
根据本发明的实施方案，对所述熟化的时间没有特别的限定，其可以为本领域技术人员已知的操作进行即可，从上述关于本申请的方法的机理描述可以看出，熟化的过程可以理解为无定型物的成核与生长或单晶形成与生长的过程，适当的延长熟化的时间，可以获得颗粒尺寸、形态完整的单晶或无定型物，但需要注意的是，由于调节熟化时间的本质是对拟结晶物质的聚集浓度进行调控，过久的熟化可能会导致聚集浓度过高，反而不利于形成无定型物或单晶。示例性地，所述熟化的时间为大于1皮秒，优选地，所述熟化的时间为1～1000分钟，还优选地，所述熟化的时间为10～300分钟。
示例性地，所述熟化的时间小于25min，通过与熟化过程的升温或降温速率进行调控，可以实现无定型物的制备。所述熟化的时间大于等于25min时，可以进一步对拟结晶物质的聚集浓度进行调控，例如可以制备得到单晶。但是所述熟化的时间也不能过长，过长的熟化时间可能会使已得到的单晶进一步变成多晶结构。
根据本发明的实施方案，熟化过程可以为采用任意制冷装置或采用任意低温，使拟结晶物质的水溶液仍保持冻结状态即可；例如采用压缩制冷设备、半导体制冷设备、或采用液氮、液氦、液态二氧化碳、液态氧、液态乙烷、干冰、冰等中的一种或几种方法的组合。
根据本发明的实施方案，在步骤(a3)中，所述冰的分离可以采用物理方式和/或化学方式将冰进行分离。冻结或任选进一步熟化结束后已经制备得到单晶或无定型物，此时的单晶或无定型物是存在于冰界面处的，需要通过适当的方法将其分离开；或者是将冰去除。
根据本发明的实施方案，所述的物理方式包括但不限于机械分离、升华(如真空升华)中的一种或几种方式的组合。所述升华例如可以利用冷冻干燥的方式进行；所述真空升华例如可以利用真空条件下的冷冻干燥的方式进行。
根据本发明的实施方案，所述的化学方式包括但不限于化学反应、电解中的一种或几种方式的组合。
根据本发明，所述方法还包括如下步骤：
(a4)收集步骤(a3)制备得到的单晶或无定型物。
根据本发明的实施方案，在步骤(a4)中，所述收集包括但不限于采用光学显微镜收集、扫描电子显微镜收集、双束电子显微镜收集、透射电子显微镜收集中的一种或几种的组合。
[培养单晶的方法]
如前所述，本发明还提供一种培养单晶的方法，所述方法包括上述的制备单晶的方法。
根据本发明的实施方案，所述培养单晶的方法还包括如下步骤：
(b1)将上述制备的拟结晶物质的单晶转移到拟结晶物质的母液中进行培养；
(b2)对步骤(b1)的单晶进行收集。
根据本发明的实施方案，所述的转移为本领域技术人员知晓的任意一种能够移取单晶的方法，包括但不限于光学显微镜移取、扫描电子显微镜移取、双束电子显微镜移取、透射电子显微镜移取中的一种或几种的组合。
根据本发明的实施方案，所述的母液为本领域技术人员知晓的与待培养的单晶相适配的母液体系。
以下通过具体实施方式针对本发明作进一步的详细说明，但不应将此理解为本发明的范围仅限于以下具体的实施例。在不脱离本发明思想的情况下，对下列技术方案做出的各种替换或变更，均应包含在本发明的范围内。
下述实施例中所述的熟化时间是指冻结过程结束后，升温或降温至熟化温度所需的时间，以及在熟化温度下维持的时间；所述的维持时间是指在熟化温度下维持的时间。
实施例1
用超纯水配制浓度为500μM的硫酸铜溶液，用量筒取100ml的溶液至烧杯中，将其放置于-24℃冰箱中缓慢降温至完全结冰，最后将其置于-15℃冰箱中熟化30min，随后冷冻干燥样品，完全升华固态冰，便可得到单晶。最后从烧杯中选取质量较好的单晶移至饱和硫酸铜水溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的硫酸铜晶体，检测结果见附图1。由图1可知，所得晶体为单晶。
实施例2
用超纯水配制浓度为10mM的硫酸铜溶液，用注射器取30μL的溶液，将其铺展在硅片上，放置-24℃冰箱中缓慢降温至完全结冰，最后将其置于-18℃冰箱中熟化40min，随后骤冷去除冰，便可得到单晶。最后从硅片中选取质量较好的单晶移至饱和硫酸铜水溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的硫酸铜晶体。
实施例3
用超纯水配制浓度为6mM的硫酸铜溶液，用移液枪取15μL的溶液，将其滴落至-90℃的硅片，硅片温度通过冷热台控制，随即以15℃/min的升温速率，升至-25℃，在此温度下维持40min。随后冷冻干燥样品，完全升华固态冰，随之从硅片中选取质量较好的单晶移至饱和硫酸铜水溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的硫酸铜晶体。
实施例4
用超纯水配制浓度50mM的谷氨酸溶液，用量筒取100ml的溶液至烧杯中，将其放置于-24℃冰箱中缓慢降温至完全结冰，最后将其置于-20℃冰箱中熟化15min，随后冷冻干燥样品，完全升华固态冰，便可得到单晶。最后从烧杯中选取质量较好的单晶移至饱和谷氨酸水溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的谷氨酸晶体，检测结果见附图2。由图2可知，所得晶体为单晶。
实施例5
用超纯水配制浓度为1M的苄基青霉素溶液，用量筒取100ml的溶液至烧杯中，将其放置于-24℃冰箱中缓慢降温至完全结冰，最后将其置于-15℃冰箱中熟化30min，随后冷冻干燥样品，完全升华固态冰，便可得到单晶。最后从烧杯中选取质量较好的单晶移至饱和苄基青霉素水溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的苄基青霉素晶体，检测结果见附图3。由图3可知，所得晶体为单晶。
实施例6
用超纯水配制浓度为10mM的苄基青霉素溶液，用移液枪取15μL的溶液，将其滴落至-90℃的硅片， 硅片温度通过冷热台控制，随即以5℃/min的升温速率，升至-25℃，在此温度下维持60min。随后冷冻干燥样品，完全升华固态冰，随之从硅片中选取质量较好的单晶移至饱和苄基青霉素溶液，置于温度为25℃，相对湿度为40％的恒温恒湿环境下一段时间，便可长出体积更大的苄基青霉素晶体。
实施例7-55
操作步骤同实施例1，区别如下表所示：
Figure PCTCN2019114136-appb-000001
Figure PCTCN2019114136-appb-000002
Figure PCTCN2019114136-appb-000003
Figure PCTCN2019114136-appb-000004
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种利用水溶液制备单晶或无定型物的方法，所述方法包括以下步骤：
    (a1)配制拟结晶物质的水溶液；
    (a2)对步骤(a1)的拟结晶物质的水溶液进行冻结；
    任选地进行熟化，制备得到含有拟结晶物质的单晶或无定型物和冰的混合体系；
    任选地，(a3)分离步骤(a2)的拟结晶物质的单晶或无定型物和冰的混合体系，得到拟结晶物质的单晶或无定型物。
  2. 根据权利要求1所述的方法，其特征在于，所述方法包括以下步骤：
    (a1)配制拟结晶物质的水溶液；
    (a2)对步骤(a1)的拟结晶物质的水溶液进行冻结，任选地进行熟化，制备得到含有拟结晶物质的单晶和冰的混合体系，
    任选地，(a3)从步骤(a2)的混合体系中分离得到拟结晶物质的单晶；
    其中，所述熟化的过程中升温或降温速率小于10℃/min，和/或，所述熟化的过程中熟化的时间至少为25min；
    优选地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，保持一段时间，即得到含有拟结晶物质的单晶和冰的混合体系；
    优选地，在熟化过程中，将温度以任意升温或降温速度达到某一温度，熟化至少25min，即得到含有拟结晶物质的单晶和冰的混合体系；
    优选地，在熟化过程中，将温度以小于10℃/min的升温或降温速度达到某一温度，熟化至少25min，即得到含有拟结晶物质的单晶和冰的混合体系。
  3. 根据权利要求1所述方法，其特征在于，所述方法包括如下步骤：
    (a1)配制拟结晶物质的水溶液；
    (a2)对步骤(a1)的拟结晶物质的水溶液进行冻结，熟化，制备得到含有拟结晶物质的无定型和冰的混合体系；任选地，
    (a3)从步骤(a2)的混合体系中分离得到拟结晶物质的无定型；
    其中，所述熟化的过程中升温或降温速率大于等于10℃/min，所述熟化的过程中熟化的时间小于25min。
  4. 根据权利要求1-3任一项所述方法，其特征在于，所述水包括但不限于超纯水、二次水、去离子水。
  5. 根据权利要求1-4任一项所述的方法，其特征在于，步骤(a1)中，所述拟结晶物质包括但不限于无机物和/或有机物；
    优选地，所述拟结晶物质在水中的溶解度为难溶、微溶、可溶或易溶。
  6. 根据权利要求1-5任一项所述的方法，其特征在于，在步骤(a2)中，所述冻结是将步骤(a1)的拟结晶物质的水溶液采用任意冻结方法、通过任意冻结过程由液态转变为固态；
    优选地，所述冻结的方法包括但不限于采用压缩制冷设备降温冻结、半导体制冷设备降温冻结、液氮降温冻结、液氦降温冻结、液态二氧化碳降温冻结、液态氧降温冻结、液态乙烷降温冻结、干冰降温冻 结、冰降温冻结等中的一种或几种降温冻结方法的组合；
    优选地，所述冻结的过程包括但不限于快速降温、缓慢降温、分步降温、先升温后降温等中的一种或者几种冻结过程的组合；
    优选地，所述冻结包括但不限于完全冻结，未完全冻结。
  7. 根据权利要求1-6任一项所述的方法，其特征在于，所述熟化为将冻结成固体的拟结晶物质的水溶液维持在固体状态一段时间。
  8. 根据权利要求1-7任一项所述的方法，其特征在于，在步骤(a3)中，所述分离包括但不限于物理方式和/或化学方式；
    优选地，所述的物理方式包括但不限于机械分离、升华、溶解、吸附中的一种或几种方式的组合；
    优选地，所述的化学方式包括但不限于化学反应、电解中的一种或几种方式的组合；
    优选地，所述方法还包括如下步骤：(a4)收集步骤(a3)制备得到的单晶；
    优选地，在步骤(a4)中，所述收集包括但不限于采用光学显微镜收集、扫描电子显微镜收集、双束电子显微镜收集、透射电子显微镜收集中的一种或几种的组合。
  9. 一种培养单晶的方法，其特征在于，所述方法包括权利要求1-7任一项所述制备单晶的方法；
    优选地，所述方法还包括如下步骤：
    (b1)将权利要求1-8任一项所述制备单晶的方法制备的拟结晶物质的单晶转移到拟结晶物质的母液中进行培养；任选地，
    (b2)对步骤(b1)培养的单晶进行收集。
  10. 根据权利要求9所述的方法，其特征在于，在步骤(b1)中，所述的转移可以是将步骤(a2)的含有拟结晶物质的单晶和冰的混合体系转移到拟结晶物质的母液中进行单晶培养；或者是将步骤(a3)的去除冰后的单晶直接转移到拟结晶物质的母液中进行单晶培养；或者是将步骤(a4)收集到的单晶转移到拟结晶物质的母液中进行单晶培养；
    优选地，所述的转移包括但不限于光学显微镜移取、扫描电子显微镜移取、双束电子显微镜移取、透射电子显微镜移取中的一种或几种的组合；
    优选地，在步骤(b1)中，所述单晶的培养方法包括但不限于蒸发法、降温法、扩散法中的一种或几种的组合；优选地，在步骤(b2)中，所述收集包括但不限于采用光学显微镜收集、扫描电子显微镜收集、双束电子显微镜收集、透射电子显微镜收集中的一种或几种的组合。
PCT/CN2019/114136 2018-10-30 2019-10-29 一种利用水溶液制备单晶或无定型物的方法 WO2020088479A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811279252 2018-10-30
CN201811279252.7 2018-10-30

Publications (1)

Publication Number Publication Date
WO2020088479A1 true WO2020088479A1 (zh) 2020-05-07

Family

ID=68895461

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/114136 WO2020088479A1 (zh) 2018-10-30 2019-10-29 一种利用水溶液制备单晶或无定型物的方法

Country Status (2)

Country Link
CN (1) CN110607552B (zh)
WO (1) WO2020088479A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020088480A1 (zh) * 2018-10-30 2020-05-07 中国科学院化学研究所 一种利用溶液冻结制备单晶或无定型物的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028958A1 (en) * 1999-10-22 2001-04-26 Technische Universiteit Delft Crystallisation of materials from aqueous solutions
CN1731984A (zh) * 2003-01-15 2006-02-08 陶氏环球技术公司 通过在冷表面上冰冻得到的药物粒子
CN101397329A (zh) * 2007-09-25 2009-04-01 重庆人本药物研究院 罗库溴铵结晶水合物的制备方法
RU2530093C1 (ru) * 2013-05-15 2014-10-10 Федеральное государственное автономное образовательное учреждение высшего образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) Способ получения монокристаллов солей серотонина кристаллизацией из водных растворов
CN104610411A (zh) * 2015-01-08 2015-05-13 浙江华海药业股份有限公司 一种化合物的纯化方法
CN104695023A (zh) * 2015-02-14 2015-06-10 河北科技大学 一水合四氢吡咯-2-羧酸单晶及其制备方法
CN106317035A (zh) * 2015-06-23 2017-01-11 中美华世通生物医药科技（武汉）有限公司 恩格列净单晶及其制备方法和用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG47101A1 (en) * 1992-07-31 1998-03-20 Us Bioscience Crystalline amifostine compositions and methods for the preparation and use of same
WO2009091053A1 (ja) * 2008-01-17 2009-07-23 Sosho, Inc. 結晶製造方法、凍結結晶製造方法、結晶、結晶構造解析方法、結晶化スクリーニング方法、結晶化スクリーニング装置
CN101647783B (zh) * 2009-07-24 2010-12-22 上海复旦复华药业有限公司 一种用冻干法制备注射用还原型谷胱甘肽时的预冻方法
CN102552149B (zh) * 2012-03-02 2013-03-20 海南灵康制药有限公司 一种注射用肝素钙脂质体制剂

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028958A1 (en) * 1999-10-22 2001-04-26 Technische Universiteit Delft Crystallisation of materials from aqueous solutions
CN1731984A (zh) * 2003-01-15 2006-02-08 陶氏环球技术公司 通过在冷表面上冰冻得到的药物粒子
CN101397329A (zh) * 2007-09-25 2009-04-01 重庆人本药物研究院 罗库溴铵结晶水合物的制备方法
RU2530093C1 (ru) * 2013-05-15 2014-10-10 Федеральное государственное автономное образовательное учреждение высшего образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) Способ получения монокристаллов солей серотонина кристаллизацией из водных растворов
CN104610411A (zh) * 2015-01-08 2015-05-13 浙江华海药业股份有限公司 一种化合物的纯化方法
CN104695023A (zh) * 2015-02-14 2015-06-10 河北科技大学 一水合四氢吡咯-2-羧酸单晶及其制备方法
CN106317035A (zh) * 2015-06-23 2017-01-11 中美华世通生物医药科技（武汉）有限公司 恩格列净单晶及其制备方法和用途

Also Published As

Publication number Publication date
CN110607552A (zh) 2019-12-24
CN110607552B (zh) 2024-02-20

Similar Documents

Publication Publication Date Title
WO2020088479A1 (zh) 一种利用水溶液制备单晶或无定型物的方法
CN110735176B (zh) 一种制备配位化合物单晶或无定型物的方法
CN110607551B (zh) 一种制备食品添加剂单晶或无定型物的方法
WO2020088481A1 (zh) 一种制备药物或药物中间体单晶或无定型物的方法
CN111087404A (zh) 一种基于物理气相沉积的p型与n型有机半导体共晶材料及制备方法
CN111533944B (zh) 一种可控微结构的聚酰亚胺纳米纤维气凝胶的制备方法
CN111118595B (zh) 一种利用界面反应制备单晶的方法
WO2020088480A1 (zh) 一种利用溶液冻结制备单晶或无定型物的方法
CN102560678B (zh) 一种抑制4-(4-二甲基氨基苯乙烯基)甲基吡啶对甲苯磺酸盐晶体生长过程中出现杂晶的方法
CN110606868A (zh) 一种制备多肽或蛋白质单晶或无定型物的方法
CN117779203B (zh) 一种n-苄基-2-甲基-4-硝基苯胺单晶及其制备方法和应用
CN112573547B (zh) 一种纳米碳酸锂的制备方法
CN110616463B (zh) 一种制备有机半导体分子单晶或无定型物的方法
CN118291124A (zh) 一种超小粒径的aie纳米颗粒的制备方法
CN117926424A (zh) 一种有机铵盐晶体的液相外延生长方法及有机铵盐晶体
CN114437130B (zh) 环磷酰胺的精制方法
Maruyama Electron-Microscope Study of the Ice Crystal Nuclei
CN111172594A (zh) 一种电刺激诱导制备单晶的方法
CN117701033A (zh) 一种聚乙烯醇修饰的氧化石墨烯纳米片及其制备方法和应用
CN115350141A (zh) 一种注射用头孢唑林钠的制备方法
SUZUKI et al. Freeze-drying of cephalothin sodium: granularly agglomerated crystallization during freezing. II
CN118108824A (zh) 一种调控丝素蛋白α-螺旋和β-折叠构象转变的方法
CN111733450A (zh) 改善液相外延大尺寸石榴石单晶薄膜厚度均匀性的方法及采用该方法制得的单晶薄膜
CN117062496A (zh) 定位定向生长红荧烯纳米线的方法及纳米线和应用
JP6186236B2 (ja) アミノ酸の製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19880376

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19880376

Country of ref document: EP

Kind code of ref document: A1