WO2020088481A1 - Method for preparing drug or drug intermediate single crystal or amorphous substance - Google Patents

Abstract

Disclosed is a method for preparing a drug or drug intermediate single crystal or amorphous substance. The method uses solution freezing to induce drug or drug intermediate nucleation and crystallisation, wherein the crystallisation of a dissolved drug or drug intermediate is achieved during the solution freezing, to rapidly and effectively prepare a drug or drug intermediate single crystal or amorphous substance. The method solves the problem in traditional drug or drug intermediate single crystal growth of it being difficult to crystallise a molecule single crystal or amorphous substance. The method achieves for the first time acquisition of a drug or drug intermediate single crystal or amorphous substance under very low solution concentrations, and also solves problems such as it being difficult to control single crystal formation and easy to form multiple crystals or twin crystals under high concentrations due to the fact that aggregation of drug or drug intermediates is too quick. The method has a wide application range, and is applicable to existing drug or drug intermediates.

Description

Method for preparing single crystal or amorphous substance of medicine or medicine intermediate

This application requires the priority of the prior application for the patent application number 2018112806394 submitted to the State Intellectual Property Office of China on October 30, 2018. The name of the invention is "a method for preparing and cultivating single crystals of drugs or pharmaceutical intermediates." The entire text of the prior application is incorporated into this application by reference.

Technical field

The present invention relates to the technical field of preparation of single crystals or amorphous materials, and in particular to a method for inducing the crystallization of drugs or drug intermediates or the formation of amorphous materials by freezing a solution. The method is applicable to any drug or drug that can be dissolved in a solvent Preparation of single crystals or amorphous forms of intermediates.

Background technique

Medicines, whether they are natural medicines (such as plant medicines, antibiotics, biochemical medicines, etc.), synthetic medicines or genetically engineered medicines, in terms of their chemical nature, they are composed of chemical elements such as C, H, O, N, S, etc. Goods. However, drugs are not just general chemicals. They are special chemicals used by organisms to prevent, treat, and diagnose diseases, or to regulate the functions of organisms, improve the quality of life, and maintain the health of organisms.

Drug intermediates generally refer to those key raw materials that are specifically used to produce drugs, such as the key intermediates used to produce cephalosporin 6-APA (6-aminopenicillanic acid), 7-ACA (7-amino Cephalosporanic acid) and 7-ADCA (7-aminodeacetoxycephalosporanic acid), various cephalosporin side chains, and piperazine and its derivatives used in the production of quinolones, excluding those used Basic chemical raw materials for pharmaceutical production, such as ethanol and acetic acid.

At present, the methods of crystallization of drugs or drug intermediates are widely studied. Common methods include slow solvent evaporation, temperature reduction, liquid phase diffusion, and gas phase diffusion. However, the above methods generally have the problems of poor controllability of crystal nucleation and growth, and easy occurrence of polycrystals or twins. It is well known in the art that high purity drugs or drug intermediates are critical to improving the quality of human life. Therefore, how to efficiently prepare the perfect single crystal of drug or drug intermediate is of great significance to industrial production and basic research. In addition, amorphous drugs or amorphous drug intermediates can be better absorbed by the human body, which is also of great significance for pharmaceutical industry production and basic research.

Summary of the invention

In view of the shortcomings of the prior art in the preparation method of single crystals or amorphous substances of drugs or drug intermediates, the present invention aims to provide a method for controlling the drugs or drug intermediates by freezing and optionally curing the drugs or drug intermediate solutions The supply and aggregation rate of the body to prepare a method for preparing a single crystal or amorphous substance of a drug or drug intermediate; the present invention realizes the controllable preparation of a single crystal or amorphous substance of a drug or drug intermediate by freezing the solution for the first time, namely By controlling the freezing and optionally aging process of the drug or drug intermediate solution, the supply rate and the aggregation rate of the drug or drug intermediate (that is, the drug or drug intermediate) can be adjusted, thereby regulating whether the drug or drug intermediate can become Nuclear crystallization and crystal growth, to achieve efficient preparation of single crystals or amorphous substances of drugs or drug intermediates.

The purpose of the present invention is achieved by the following technical solutions:

A method for preparing a single crystal or an amorphous substance of a drug or a drug intermediate, the method includes the following steps:

(a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

(a2) freezing the solution of the drug or drug intermediate in step (a1) and optionally aging to prepare a mixed system containing a single crystal or amorphous substance containing the drug or drug intermediate and a frozen solvent; optionally ,

(a3) Separate the single crystal or amorphous substance of the drug or drug intermediate from the mixed system of step (a2).

In the present invention, controlling the temperature of aging can also realize the preparation of single crystals or amorphous materials of drugs or drug intermediates with adjustable particle size, that is, the particle size of the single crystals or amorphous materials of the isolated drugs or drug intermediates varies with As the temperature of aging increases, it increases.

In the present invention, the freezeable solvent refers to a solvent that can form a solid at a certain temperature and a certain pressure.

In the present invention, the drugs include natural drugs (plant drugs, antibiotics, biochemical drugs), synthetic drugs and genetically engineered drugs.

Further, the medicines include medicines for the human body, including but not limited to: antibiotic medicines, cardiovascular and cerebrovascular medicines, digestive system medicines, respiratory system medicines, urinary system medicines, blood system medicines, facial medicine medicines, anti-rheumatic medicines Drugs, diabetes drugs, hormone drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins, etc.

The medicines also include medicines for animals and plants, including but not limited to: antimicrobial medicines, antiparasitic medicines, disinfection and antiseptic medicines, medicines acting on the central nervous system, medicines acting on the plant nervous system, anesthetics and their Auxiliary drugs, corticosteroid drugs, digestive system drugs, respiratory system drugs, urinary system drugs, circulatory system drugs, reproductive system drugs, blood and hematopoietic system disease drugs, vitamins and minerals, regulating water, electrolytes and acids Alkali balance drugs, antidote and anti-allergy drugs, topical drugs and pharmaceutical excipients, probiotics, plant growth regulators, insecticides, fungicides, etc.

The drug intermediate refers to a compound that can prepare the above drug. Including compounds for preparing antibiotic drugs, compounds for preparing cardiovascular and cerebrovascular drugs, compounds for preparing digestive system drugs, compounds for preparing respiratory system drugs, compounds for preparing urinary system drugs, compounds for preparing blood system drugs, and compounds for preparing facial medicine , Compounds for preparing anti-rheumatic drugs, compounds for preparing diabetes drugs, compounds for preparing hormone drugs, compounds for preparing dermatological drugs, compounds for preparing gynecological drugs, compounds for preparing antitumor drugs, compounds for preparing antipsychotic drugs, preparation Compounds for nervous system drugs, compounds for preparing vitamins, etc.

In the present invention, the solubility of the drug or drug intermediate in the solvent is easily soluble, soluble, slightly soluble or hardly soluble.

In the present invention, the step (a2) specifically includes the following steps:

The solution of the drug or drug intermediate in step (a1) is cooled and frozen into a solid mixture, and optionally subjected to aging treatment to prepare the mixed system.

In step (a2) of the present invention, the freezing is to convert the solution of the drug or drug intermediate in step (a1) from a liquid state to a solid state.

In the present invention, the freezing method includes but is not limited to natural cooling freezing, 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 and freezing, dry ice cooling and freezing, ice cooling and freezing, one or a combination of several cooling methods.

In the present invention, 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.

In the present invention, the freezing includes but is not limited to complete freezing and incomplete freezing.

In the present invention, the aging process means that the solution of the drug or drug intermediate stays in a frozen state for a period of time.

In the present invention, the aging time refers to the time required to raise the temperature to the aging temperature after the freezing process is completed, and the time maintained at the aging temperature.

In one embodiment, in the step (a2), the solution of the drug or drug intermediate in step (a1) is frozen to prepare a mixed system containing a single crystal of the drug or drug intermediate and a frozen solvent.

In one embodiment, the step (a2) includes a curing process, that is, the step (a2) freezes and cures the solution of the drug or drug intermediate in step (a1) to prepare a drug or drug Mixed system of single crystal or amorphous substance of intermediate and frozen solvent.

In one embodiment, in the step (a2), during the curing process, 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. Mixed system of amorphous substance of drug or drug intermediate and frozen solvent.

In one embodiment, the greater the difference between reaching a certain temperature 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.

In one embodiment, in the step (a2), during the curing process, 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 Mixed system containing single crystal of drug or drug intermediate and frozen solvent.

Exemplarily, during the curing process, the temperature is raised to a certain temperature at a heating or cooling rate of less than 10 ° C./min for a period of time to prepare a mixed system containing a single crystal of a drug or a drug intermediate and a frozen solvent.

Exemplarily, during the curing process, the temperature is increased to a certain temperature at an arbitrary heating or cooling rate for at least 25 minutes, and a mixed system containing a single crystal of a drug or a drug intermediate and a frozen solvent is prepared.

Exemplarily, during the curing process, the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min, and the curing is performed for at least 25 minutes to prepare a mixed system containing a single crystal of a drug or a drug intermediate and a frozen solvent.

In the present invention, in step (a3), the separation is to physically and / or chemically separate the solvent frozen into a solid from the mixed system.

In the present invention, the physical methods include but are not limited to one or a combination of several methods of quenching separation, sublimation (such as vacuum sublimation), and dissolution.

In the present invention, the chemical methods include but are not limited to one or a combination of several methods in chemical reaction and electrolysis.

In the present invention, the method further includes the following steps:

(a4) The single crystal or amorphous prepared in step (a3).

In the present invention, in step (a4), 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 of a drug or a drug intermediate. The method includes the above method for preparing a single crystal.

In the present invention, the method for culturing a single crystal of a drug or a drug intermediate further includes the following steps:

(b1) Transfer the single crystal of the drug or drug intermediate prepared above to the mother liquid of the drug or drug intermediate for cultivation;

(b2) Collect the single crystal of step (b1).

In the present invention, in step (b1), the transfer may be performed by transferring the mixed system of the single crystal containing the drug or drug intermediate and the frozen solvent in step (a2) to the mother liquid of the drug or drug intermediate Single crystal culture; or the transfer may be the single crystal after removing the solvent in step (a3) is directly transferred to the mother liquor of the drug or drug intermediate for single crystal culture; or the single crystal collected in step (a4) The crystal is transferred to the mother liquor of the drug or drug intermediate for single crystal culture.

In the present invention, 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.

In the present invention, in step (b1), 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.

In the present invention, in step (b2), 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.

Beneficial effect

1. In view of the shortcomings of molecular supply, aggregation and nucleation speed that are difficult to control in the process of preparing single crystals or amorphous materials of drugs or drug intermediates by traditional methods, the present invention proposes for the first time that solution freezing induces nucleation of drugs or drug intermediate With crystallization methods. By regulating the freezing process of the frozen drug or drug intermediate solution, and optionally the aging process, the single crystal or amorphous substance of the drug or drug intermediate is quickly and efficiently prepared. Moreover, by controlling the curing temperature, the particle size of the prepared single crystal or amorphous substance of the drug or drug intermediate can be controlled. At the same time, the method can solve the problem of preparing single crystals that are difficult to crystallize molecules in traditional single crystal preparation and culture, and can also solve the problem that some substances are difficult to form amorphous, especially high-purity amorphous.

2. Compared with the traditional evaporation method or temperature-reducing crystallization method, the freezing treatment method adopted by the present invention makes the solution concentration control range of the drug or drug intermediate larger, and the drug or drug intermediate can be realized from a very low concentration to a supersaturated concentration Preparation of single crystal or amorphous material. For the first time, the single crystal or amorphous substance of the drug or drug intermediate is obtained at a very low solution concentration; at the same time, the single crystal formation caused by the excessive aggregation of the drug or drug intermediate at high concentration is not easy to control and easy to form Crystals, twins, etc .; in addition, the present invention also has the advantage of obtaining a single crystal or amorphous substance of a drug or drug intermediate in a very short time (a few minutes to several hours).

3. In the present invention, solution freezing is a key technical point. The freezing process refers to freezing the solution in an arbitrary manner, and the freezing time, freezing temperature, freezing temperature gradient, freezing method, freezing process, etc. are not particularly limited. Experiments have confirmed that the essence of preparing solute single crystals or amorphous materials by solution freezing is that during the freezing process, the solvent freezes into a solid state (such as water molecules forming ice crystals), and the drug or drug intermediate is released and aggregates in the solid state At the interface of the solvent (such as the ice crystal interface), through the regulation of the solvent crystallization process and the recrystallization process of the crystallized solvent (such as the regulation of the water crystallization process and the ice crystal recrystallization process), thereby further regulating the drug or drug intermediate The release and aggregation rate of the body can effectively control the nucleation and growth of the drug or drug intermediate, and then obtain the single crystal or amorphous substance of the target molecule.

4. The aging process in the present invention refers to keeping the frozen solution in a solid state or a solid-liquid mixed state for a certain period of time. The temperature is not limited, but the rate of temperature increase or decrease needs to be controlled. Experiments have confirmed that the aging process described in the present invention is optionally used as a supplement to the freezing process to optimize the regulation of solute crystal recrystallization, thereby regulating the release rate of the drug or drug intermediate in the crystallized solvent and the drug or drug intermediate The rate of aggregation at the interface of the crystalline solvent is conducive to further optimizing the growth of amorphous and / or nucleation and growth of single crystals after the solution is frozen. Not only that, 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 amorphous or single crystals with higher efficiency is conducive to the reduction of energy consumption, thereby greatly saving costs. Compared with the traditional method, the present invention realizes the optimal control of the recrystallization of the crystallized solvent by adjusting the heating or cooling rate of the aging process, and can further control the aggregation of the drug or drug intermediate in the crystallized solvent to the interface of the crystallized solvent Speed, and then effectively obtain single crystals or amorphous materials of drugs or drug intermediates, which has advantages such as energy saving, and is more conducive to large-scale industrial production of amorphous or single crystals of target molecules.

5. The preparation method of the amorphous or single crystal provided by the present invention and the further single crystal cultivation method have a wide range of application, and are applicable to existing drugs or drug intermediates. In addition, the method can also be used to implement traditional methods Single crystal acquisition of substances that are difficult to crystallize, and amorphous substances that are difficult to obtain amorphous substances. And 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.

6. The solvent of the present invention is convenient to choose, whether it is a polar or non-polar solvent, as long as it can be frozen. This provides different options for the dissolution of different molecules. Especially for drugs or drug intermediates that are soluble in water systems, the use of a large number of organic solvents is eliminated, which not only reduces costs, but also has advantages such as environmental protection.

BRIEF DESCRIPTION

Figure 1 is a scanning electron micrograph and molecular formula of chloramphenicol single crystal.

Figure 2 is a scanning electron micrograph and molecular formula of a single crystal of penicillin G sodium salt.

Figure 3 is a scanning electron micrograph and molecular formula of carbenicillin disodium salt single crystal.

Fig. 4 is a scanning electron micrograph and molecular formula of nafcillin sodium monohydrate single crystal.

5 is a scanning electron micrograph and molecular formula of ginsenoside Rh ₂ single crystal.

6 is a scanning electron micrograph and molecular formula of ginsenoside Rd single crystal.

7 is a scanning electron micrograph and molecular formula of ginsenoside Rb ₂ single crystal.

8 is a scanning electron micrograph and molecular formula of gibberellin A ₁ single crystal.

9 is a scanning electron micrograph and molecular formula of gibberellin A ₅ single crystal.

Figure 10 is a scanning electron micrograph of baicalin single crystal.

Fig. 11 is a scanning electron micrograph of baicalin single crystal.

Figure 12 is a scanning electron micrograph of baicalein single crystal.

Fig. 13 is a scanning electron micrograph of β-sitosterol single crystal.

Fig. 14 is a scanning electron micrograph and molecular formula of rapeseed sterol single crystal.

Figure 15 is a scanning electron micrograph and molecular formula of jasmonic acid single crystal.

Fig. 16 is a scanning electron micrograph of p-toluenesulfonic acid single crystal.

17 is a schematic diagram of the preparation of a single crystal of the drug or drug intermediate of the present invention.

Fig. 18 is a process diagram of AIE35 forming a single crystal.

Fig. 19 is a diagram showing the process of forming single crystal of p-toluenesulfonic acid.

Figure 20 is a transmission electron micrograph and molecular formula of paclitaxel amorphous nanoparticles, scale-100nm.

FIG. 21 is a transmission electron microscope photograph and molecular formula of the amorphous nanoparticles of Myritinib, with a scale of -100 nm.

Figure 22 is a transmission electron micrograph and molecular formula of gefitinib amorphous nanoparticles, scale-100nm.

Figure 23 is a transmission electron micrograph and molecular formula of imatinib amorphous nanoparticles, scale-100nm.

Figure 24 is a transmission electron micrograph and molecular formula of camptothecin amorphous nanoparticles, scale-100nm.

Figure 25 is a transmission electron micrograph and molecular formula of griseofulvin amorphous nanoparticles, scale-100nm.

Figure 26 is a transmission electron micrograph and molecular formula of celecoxib amorphous nanoparticles, scale-100nm.

Figure 27 is a transmission electron micrograph and molecular formula of sirolimus amorphous nanoparticles, scale-100nm.

Fig. 28 is a transmission electron microscope photograph and molecular formula of aripipent amorphous nanoparticles, scale-100nm.

Fig. 29 is a transmission electron microscope photograph and molecular formula of fenofibrate amorphous nanoparticles, scale-100nm.

Figure 30 is a transmission electron micrograph and molecular formula of amorphous nanoparticles of nepafenac, scale-100nm.

Figure 31 is a transmission electron microscope photograph and molecular formula of amorphous nanoparticles of dantrolene sodium, scale-100nm.

Figure 32 is a transmission electron microscope photograph and molecular formula of paliperidone palmitate amorphous nanoparticles, scale-100nm.

Figure 33 is a transmission electron micrograph and molecular formula of 10-hydroxycamptothecin amorphous nanoparticles, scale-100nm.

Figure 34 is a transmission electron microscope photograph and molecular formula of amorphous progesterone nanoparticles, scale-100nm.

Figure 35 is a scanning electron micrograph and molecular formula of paclitaxel single crystal nanoparticles.

Figure 36 is the particle size distribution of paclitaxel single crystal nanoparticles in suspension.

Figure 37 is a transmission electron micrograph of paclitaxel amorphous nanoparticles.

Figure 38 is the particle size distribution of paclitaxel amorphous nanoparticles in suspension.

Figure 39 is a scanning electron micrograph of paclitaxel single crystal nanoparticles.

Figure 40 is the particle size distribution of paclitaxel single crystal nanoparticles in suspension.

Figure 41 is a transmission electron micrograph and molecular formula of paclitaxel amorphous nanoparticles.

Figure 42 is the particle size distribution of paclitaxel amorphous nanoparticles in suspension.

43 is a scanning electron micrograph of 10-hydroxycamptothecin single crystal nanoparticles of Example 42.

44 is the particle size distribution of 10-hydroxycamptothecin single crystal nanoparticles in suspension in Example 42. FIG.

45 is a transmission electron micrograph of 10-hydroxycamptothecin amorphous nanoparticles of Example 42.

46 is the particle size distribution of the 10-hydroxycamptothecin amorphous nanoparticles in Example 42 in suspension.

47 is a scanning electron micrograph of camptothecin single crystal nanoparticles of Example 45.

48 is the particle size distribution of camptothecin single crystal nanoparticles in Example 45 in suspension.

49 is a transmission electron micrograph of the camptothecin amorphous nanoparticles of Example 45.

50 is the particle size distribution of the camptothecin amorphous nanoparticles in Example 45 in suspension.

51 is a scanning electron micrograph of irinotecan single crystal nanoparticles of Example 46.

52 is the particle size distribution of irinotecan single crystal nanoparticles in suspension in Example 46.

53 is a transmission electron micrograph of irinotecan amorphous nanoparticles of Example 46.

54 is the particle size distribution of irinotecan amorphous nanoparticles in Example 46 in suspension.

55 is a scanning electron micrograph of the single crystal gefitinib nanoparticles of Example 47.

56 is the particle size distribution of the single crystal gefitinib nanoparticles in Example 47 in suspension.

57 is a transmission electron microscope photograph of gefitinib nanoparticles of Example 47.

58 is the particle size distribution of the gefitinib amorphous nanoparticles of Example 47 in suspension.

detailed description

The drug or drug intermediate in the present invention refers to the presence of single crystal or amorphous substance. The drug is a drug used by any organism in order to maintain the normal operation of the organism. The organism includes but is not limited to the human body, animals and plants.

The drug intermediate is for preparing the above drug, and there is a single crystal or an amorphous substance.

In the present invention, "optionally" means to perform or not to perform subsequent steps.

In the present invention, the amorphous substance of the drug or drug intermediate is an amorphous drug or drug intermediate.

[Method of preparing single crystal or amorphous material]

As mentioned above, the present invention provides a method for preparing a single crystal or an amorphous substance of a drug or a drug intermediate. The method includes the following steps:

(a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

(a2) freezing the solution of the drug or drug intermediate in step (a1) and optionally aging to prepare a mixed system of a frozen solvent containing a single crystal or amorphous substance of the drug or drug intermediate; optionally ,

(a3) Separate the single crystal or amorphous substance of the drug or drug intermediate from the mixed system of step (a2).

[Method of preparing single crystal]

As mentioned above, the present invention provides a method for preparing a single crystal of a drug or a drug intermediate. The method includes the following steps:

(a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

(a2) freezing the solution of the drug or drug intermediate in step (a1) and optionally aging to prepare a mixed system of a frozen solvent containing a single crystal of the drug or drug intermediate; optionally,

(a3) separating the single crystal of the drug or drug intermediate from the mixed system of step (a2);

Wherein, 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.

Exemplarily, during the curing process, 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 a single-crystal frozen solvent containing a drug or drug intermediate.

Exemplarily, during the curing process, the temperature is increased to a certain temperature at an arbitrary heating or cooling rate, and the curing is performed for at least 25 minutes to obtain a mixed system of a single-crystal frozen solvent containing a drug or a drug intermediate.

Exemplarily, during the curing process, the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min, and the curing is performed for at least 25 minutes to obtain a mixed system of a single-crystal frozen solvent containing a drug or drug intermediate.

Exemplarily, 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.

As described above, the rate of temperature increase or decrease 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. 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.

As mentioned above, 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, and so on.

Exemplarily, the drug or drug intermediate is selected from at least one of the following substances:

Chloramphenicol, penicillin G sodium salt, baicalin, carbenicillin disodium salt, nafcillin sodium monohydrate, ginsenoside Rh ₂ , ginsenoside Rd, ginsenoside Rb ₂ , gibberellin A ₁ , gibberellin element A _5, baicalin, scutellarein, [beta] -sitosterol, campesterol, jasmonic acid, p-toluenesulfonic acid.

[Method of preparing amorphous]

As mentioned above, the present invention provides a method for preparing an amorphous drug or a drug intermediate. The method includes the following steps:

(a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

(a2) freezing and aging the solution of the drug or drug intermediate in step (a1) to prepare a mixed system of an amorphous frozen solvent containing the drug or drug intermediate; optionally,

(a3) Separate the amorphous form of the drug or drug intermediate from the mixed system of step (a2);

Wherein, 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.

Exemplarily, during the curing process in the step (a2), the temperature is matured at a temperature of 10 ° C./min or higher to reach a certain temperature for less than 25 minutes to obtain an amorphous product containing a drug or a drug intermediate A mixed system of frozen solvents.

In one embodiment, the greater the difference between the certain 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 temperature. Exemplarily, 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 ℃, -45 ℃, etc. Preferably, the temperature rises from the liquid nitrogen temperature to 10 ° C / min or more to the above temperature.

As mentioned above, 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 ℃ / min, 21 ℃ / min, 22 ℃ / min, 23 ℃ / min, 24 ℃ / min, 25 ℃ / min, 26 ℃ / min, 27 ℃ / min, 28 ℃ / min, 29 ℃ / 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.

Exemplarily, the drug or drug intermediate is selected from at least one of the following substances:

Paclitaxel, myritinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib, sirolimus, aprepitant, fenofibrate, nepafenac, Dantraline sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol.

[Specific scheme in the above method]

According to an embodiment of the present invention, in step (a1), the preparation of the solution of the drug or drug intermediate may be performed using an operation method known to those skilled in the art, such as a standard solution preparation method.

According to an embodiment of the present invention, in step (a1), the freezeable solvent includes but is not limited to water and / or organic solvent.

The water includes but is not limited to secondary water, distilled water, ultrapure water.

The freezeable organic solvent refers to an organic solvent that can form a solid at a certain temperature and a certain pressure.

The freezeable organic solvents include but are not limited to hydrocarbon organic solvents, halogenated hydrocarbon organic solvents, alcohol organic solvents, phenol organic solvents, ether and acetal organic solvents, ketone organic solvents, acids and anhydrides Organic solvents, ester-based organic solvents, nitrogen-containing compound-based organic solvents, sulfur-containing compound-based organic solvents, polyfunctional organic solvents, etc.

The hydrocarbon organic solvents include aliphatic hydrocarbons (linear aliphatic hydrocarbons, branched aliphatic hydrocarbons, alicyclic hydrocarbons), aromatic hydrocarbons; for example: methane, ethane, propane, butane, pentane, 2-methylbutane, Hexane, petroleum ether, butene, cyclopentane, cyclohexane, benzene, styrene, toluene, xylene, ethylbenzene, diethylbenzene, biphenyl, naphthalene, etc .; the halogenated hydrocarbon organic solvent is Halogen-substituted hydrocarbon organic solvents such as dichloromethane, chloroform, carbon tetrachloride, ethyl chloride, dichloroethane, trichloroethane, dibromomethane, bromoethane, dibromoethane, dibromopropane , Chlorobenzene, dichlorobenzene, dichlorotoluene, dibromobenzene, etc. The alcohol solvents include, for example: methanol, ethanol, propanol, isopropanol, butanol, isobutanol, amyl alcohol, 2-methyl -1-butanol, cycloethanol, phenethyl alcohol, ethylene glycol, propylene glycol, glycerin, butylene glycol, pentanediol, ethylene glycol, etc .; the phenolic solvents are, for example, phenol, hydroquinone, cresol, Xylenol and the like; the ether and acetal solvents are, for example, methyl ether, ether, methyl ethyl ether, propyl ether, ethyl butyl ether, anisole, diphenyl ether, ethylene oxide , Propylene oxide, butylene oxide, dioxane, furan, tetrahydrofuran, ethylene glycol methyl ether, ethylene glycol butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol methyl ether, glycerin Ether, crown ether, benzaldehyde, cinnamaldehyde, etc .; the ketone solvents are, for example: acetone, methyl ethyl ketone, methyl acetone, amyl ketone, cyclohexanone, acetophenone, etc .; the acid and anhydride solvents are for example: formic acid , Acetic acid, oxalic acid, propionic acid, butyric acid, acetic anhydride, propionic anhydride, etc .; the ester solvents are, for example: methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl benzoate , Ethyl benzoate, ethyl cinnamate, dimethyl phthalate, butyrolactone, etc .; the nitrogen-containing compound solvents include nitro solvents, nitrile solvents, amine solvents, amide solvents, lactams Solvents, such as: nitroethane, nitrobenzene, acetonitrile, propionitrile, methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, aniline, pyrrole, tetrahydropyrrole, piperidine, Pyridine, tetrahydropyridine, ethylenediamine, propylenediamine, formamide, acetamide, N, N-dimethylformamide, N, N-dimethylacetamide, pyrrolidone, N-methylpyrrolidone, caprolactam, etc .; the sulfur-containing compounds are, for example: carbon disulfide, methyl sulfide, thiophene, tetrahydrothiophene, dimethyl sulfoxide, di Methyl sulfone, etc .; the multifunctional solvent is, for example, ethylene glycol monomethyl ether, diethylene glycol, polyethylene glycol, polypropylene glycol, 2-chloroethanol, allyl alcohol, acrylonitrile, diethanolamine, p-methoxy Benzyl alcohol, morpholine, N-methylmorpholine, lactic acid, methyl acetoacetate, ethyl acetoacetate, etc.

According to an embodiment of the present invention, the organic solvent further includes a combination of the aforementioned multiple organic solvents.

In the present invention, the drugs include natural drugs (such as plant drugs, antibiotics, biochemical drugs, etc.), synthetic drugs or genetically engineered drugs.

Further, the medicines include medicines for the human body, including but not limited to: antibiotic medicines, cardiovascular and cerebrovascular medicines, digestive system medicines, respiratory system medicines, urinary system medicines, blood system medicines, facial medicine medicines, anti-rheumatic medicines Drugs, diabetes drugs, hormone drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins, etc.

The medicines also include medicines for animals and plants, including but not limited to: antimicrobial medicines, antiparasitic medicines, disinfection and antiseptic medicines, medicines acting on the central nervous system, medicines acting on the plant nervous system, anesthetics and their Auxiliary drugs, corticosteroid drugs, digestive system drugs, respiratory system drugs, urinary system drugs, circulatory system drugs, reproductive system drugs, blood and hematopoietic system disease drugs, vitamins and minerals, regulating water, electrolytes and acids Alkali balance drugs, antidote and anti-allergy drugs, topical drugs and pharmaceutical excipients, probiotics, plant growth regulators, insecticides, fungicides, etc.

The drug intermediate refers to a compound that can prepare the above drug. Including compounds for preparing antibiotic drugs, compounds for preparing cardiovascular and cerebrovascular drugs, compounds for preparing digestive system drugs, compounds for preparing respiratory system drugs, compounds for preparing urinary system drugs, compounds for preparing blood system drugs, and compounds for preparing facial medicine , Compounds for preparing anti-rheumatic drugs, compounds for preparing diabetes drugs, compounds for preparing hormone drugs, compounds for preparing dermatological drugs, compounds for preparing gynecological drugs, compounds for preparing antitumor drugs, compounds for preparing antipsychotic drugs, preparation Compounds for nervous system drugs, compounds for preparing vitamins, etc.

According to an embodiment of the present invention, the drug or drug intermediate may be a hydrophilic drug or a hydrophobic drug.

Exemplarily, the drug or drug intermediate is selected from at least one of the following substances: paclitaxel, myritinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib Cloth, sirolimus, aprepitant, fenofibrate, nepafenac, dantrolene sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol, chloramphenicol, Penicillin G sodium salt, baicalin, carbenicillin disodium salt, nafcillin sodium monohydrate, ginsenoside Rh ₂ , ginsenoside Rd, ginsenoside Rb ₂ , gibberellin A ₁ , gibberellin A ₅ , Baicalin, scutellarin, β-sitosterol, brassicasterol, jasmonic acid, p-toluenesulfonic acid.

According to an embodiment of the present invention, the drug or drug intermediate has a certain solubility in the solvent; those skilled in the art can understand that the amount of the drug or drug intermediate dissolved in the solvent can be any, that is The drug or drug intermediate can be dissolved in the solvent, and the amount of the drug or drug intermediate dissolved in the solvent is not particularly limited; it can be understood that the solubility of the drug or drug intermediate in the solvent may be insoluble, slightly soluble, or soluble And soluble.

According to the embodiment of the present invention, preferably, the amount of the drug or drug intermediate dissolved in the solvent is greater than or equal to 1 × 10 ^-7 g / 100g (used solvent), for example, greater than or equal to 0.001g / 100g (used solvent) , If greater than or equal to 0.01g / 100g (used solvent), if greater than or equal to 0.1g / 100g (used solvent), if greater than or equal to 1g / 100g (used solvent), if greater than or equal to 10g / 100g (used solvent).

According to the embodiment of the present invention, the concentration of the solution of the drug or drug intermediate is not particularly limited, that is, the drug or drug intermediate can be dissolved in a solvent; as known to those skilled in the art, the drug or drug intermediate The body may be an unsaturated solution, a saturated solution, or a supersaturated solution in the solvent; of course, the concentration of the solution of the drug or drug intermediate will greatly affect the aggregation rate of the drug or drug intermediate, When the concentration is low, the aggregation speed of the drug or drug intermediate is slow, and the time required to obtain the single crystal or amorphous substance will increase accordingly; when the concentration is high, the aggregation speed of the drug or drug intermediate is fast, and the single crystal or amorphous substance is obtained The time required for things will be reduced accordingly. Therefore, by reasonably selecting the concentration, 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, but also has a close relationship with aging.

According to an embodiment of the present invention, the concentration of the solution of the drug or drug intermediate is greater than or equal to 1 × 10 ^-7 g / 100g (used solvent), for example, greater than or equal to 0.001g / 100g (used solvent), such as greater than or equal to 0.01 g / 100g (solvent used), such as greater than or equal to 0.1g / 100g (solvent used), such as greater than or equal to 1g / 100g (solvent used), such as greater than or equal to 10g / 100g (solvent used). The upper limit of the concentration of the organic solvent solution of the drug or drug intermediate is not particularly limited, and it may be a supersaturated solution or a saturated solution of the drug or drug intermediate in the solvent.

Preferably, the concentration of the solution of the drug or drug intermediate is 1 × 10 ⁻⁷ g / 100 g (solvent used) to 1 g / 100 g (solvent used).

According to the present invention, the step (a2) specifically includes the following steps:

The solution of the drug or drug intermediate in step (a1) is cooled and frozen into a solid, and optionally subjected to aging treatment to prepare the obtained mixed system.

In the present invention, the inventor unexpectedly discovered that during the freezing of the solution, the solvent will freeze to a solid, and the drug or drug intermediate dissolved in the solution will achieve concentration aggregation at the solvent interface to form a single crystal or amorphous Supplies possible. In addition, the frozen drug or drug intermediate solution, when in the freezing process and optionally further ripening process, the grain size formed by the solvent will gradually increase, so that the drug or drug intermediate will be at the interface of each crystal Continue to aggregate, grow up and form amorphous or single crystal, and finally you can obtain nanoparticles with a particle size of tens of nanometers to hundreds of nanometers, as shown in Figure 17. Taking the water system as an example, in order to prove that ice crystals accumulate drugs or drug intermediates at their interfaces during freezing or optionally further ripening, we selected the aggregate luminescent material AIE35 to verify the process (the aggregate luminescent material is in the free In the molecular state, any wavelength cannot be excited to make it emit light, but when the molecule exists in an aggregated state, it will be excited to emit fluorescence). During the experiment, the AIE35 aqueous solution was frozen into a solid by any means, and ice would form separate polycrystalline systems. As shown in Figure 18, at the interface of any two ice crystals in contact, AIE35 formed aggregates, and crystallization. It can be seen from A in FIG. 18 that the fluorescence at the interface is enhanced, indicating that AIE35 molecules can aggregate at the interface and gradually form an AIE35 nanocrystalline single crystal from an amorphous substance. And from B in FIG. 18, it can be seen that the aggregate formed at the interface undergoes a transition from an amorphous state to a single crystal, and its single crystal volume gradually increases. Figure 18 shows the results of transmission electron microscopy and electron diffraction characterization.

The molecular structure of AIE35 is:

In order to further prove the principle of single crystal formation, we used p-toluenesulfonic acid molecules, and used transmission electron microscopy to attenuate total reflection infrared in situ at low temperature to observe the accumulation of p-toluenesulfonic acid during the freezing and aging of water and form single The process of growing crystals and single crystals. The 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, p-toluenesulfonic acid molecules continue to aggregate so that the formed single crystals continue to grow (see Figure 19).

According to an embodiment of the present invention, the freezing includes but is not limited to complete freezing and incomplete freezing. Those skilled in the art can understand that the complete freezing means that the solution of the drug or drug intermediate is completely frozen into a solid; the incomplete freezing means that the solution of the drug or drug intermediate is partially frozen into a solid and part is still a liquid status.

According to the embodiment of the present invention, those skilled in the art may understand that the freezing may be any one or several cooling methods to cool down a solution of a drug or drug intermediate having any volume and shape with any one or several cooling methods The process freezes it into a solid or solid-liquid mixture. That is, the freezing is to freeze the solution of the drug or drug intermediate into a solid or solid-liquid mixture. Compared with the traditional evaporation method and temperature-lowering crystallization method, the freezing crystallization method has a larger adjustment range of the solution concentration of the drug or drug intermediate, and the time required to obtain the single crystal of the drug or drug intermediate is greatly shortened.

According to an embodiment of the present invention, the freezing time, freezing temperature, freezing temperature gradient, freezing method, freezing process, etc. are not particularly limited, and a solution of a drug or drug intermediate of any volume and shape is frozen It can be a solid or solid-liquid mixture. Of course, in the freezing process, the concentration of the drug or drug intermediate solution can also be considered to make a reasonable choice. The purpose is to control the diffusion rate of the drug or drug intermediate, thereby affecting its crystallization process. Exemplarily, if the concentration of the drug or drug intermediate solution is high, 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 drug or Drug intermediates are difficult to control to form polycrystals; if the concentration of the drug or drug intermediate solution 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 drug or drug The intermediates are effectively aggregated, which in turn can form amorphous or single crystals.

According to an embodiment of the present invention, 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.

According to the embodiment of the present invention, 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.

According to an embodiment of the present invention, the freezing process is an operation mode known to those skilled in the art, for example, freezing a solution of a drug or a drug intermediate from a liquid state to a solid state by any process. Exemplarily, the freezing process Including, but not limited to, one or a combination of several types of freezing processes including rapid cooling, slow cooling, stepwise cooling, first heating and then cooling.

According to an embodiment of the present invention, the volume and shape of the solution of the drug or drug intermediate are not particularly limited; the volume and shape of the solid frozen from the solution of the drug or drug intermediate are also not particularly limited, as long as they can be It can be obtained by freezing to obtain a solid or solid-liquid mixture; those skilled in the art can understand that the freezing can be the whole freezing of a solution of any volume of drugs or drug intermediates, or the freezing of any volume of drugs or drug intermediates The film formed by the solution is frozen, or the droplets formed by the solution of any volume of the drug or drug intermediate are frozen.

According to an embodiment of the present invention, the solution of the drug or drug intermediate frozen into a solid or solid-liquid mixture may optionally be further subjected to curing treatment; the curing temperature, curing time, and curing process during the curing treatment process are not Special limitation, but it is only necessary to ensure that the solution of the drug or drug intermediate frozen during the curing process remains at least partially or completely in a solid state, that is, the solution of the drug or drug intermediate during the curing process remains frozen. ; For example, using the same method as the freezing process to cure the solid, or using other methods to cure the solid; the purpose of the curing process is to achieve the aggregation of drugs or drug intermediates and the growth rate of nanoparticles Regulation to obtain single crystal or amorphous substance of drug or drug intermediate. Those skilled in the art will appreciate, the curing temperature should be below that of the frozen solution of the drug or drug intermediate re-melting temperature (i.e. T _melt), preferably the aging temperature is lower than _melting above T 5 ℃, More preferably, the _melting temperature is lower than T by 10 ° C or higher.

According to an embodiment of the present invention, the aging process is that the solution of the drug or drug intermediate 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.

According to an embodiment of the present invention, the aging process uses, for example, rapid temperature increase (or temperature decrease) or slow temperature increase (or temperature decrease). Exemplarily, the temperature increase or decrease rate of the aging process is greater than or equal to 10 ° C / min, The heating or cooling rate in this range will quickly release the drug or drug intermediate from the solid mixture and produce disordered aggregation. By limiting the aging time, it provides a guarantee for the preparation of amorphous products.

Exemplarily, 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 the drug or drug intermediate from the solid mixture to produce ordered aggregation, and a single crystal can be prepared .

According to an embodiment of the present invention, the curing temperature (that is, a certain temperature reached) controls the size of the grains of the freezing solvent and thus controls the aggregation rate of the drug or drug intermediate, that is, the greater the temperature difference between the curing temperature and the freezing temperature , The crystal size of the frozen solvent is larger, the drug or drug intermediate aggregates faster, and the time required to form a single crystal or amorphous is shorter, then the prepared single crystal or amorphous of the drug or drug intermediate The particle size is also larger; the smaller the temperature difference between the curing temperature and the freezing temperature, the smaller the crystal size of the freezing solvent, the slower the aggregation speed of the drug or drug intermediate, the longer it takes to form a single crystal or amorphous, and the preparation The particle size of the obtained single crystal or amorphous substance of the drug or drug intermediate is also small. That is, the larger the temperature difference between the curing temperature and the freezing temperature, the larger the particle size of the prepared single crystal or amorphous substance of the drug or drug intermediate.

According to the embodiment of the present invention, there is no particular limitation on the curing time, which may be a process known to those skilled in the art. As can be seen from the foregoing mechanism description of the method of the present application, the curing process can be understood as The process of nucleation and growth of amorphous materials or the formation and growth of single crystals can prolong the curing time properly to obtain amorphous or single crystals with complete particle size and morphology, but it should be noted that due to the nature of adjusting the curing time It is to adjust the aggregation concentration of drugs or drug intermediates. Prolonged aging may lead to too high aggregation concentration, which is not conducive to the formation of amorphous or single crystal. Exemplarily, the aging time is greater than 1 picosecond, preferably, the aging time is 1-1000 minutes, further preferably, the aging time is 10-300 minutes.

Exemplarily, 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. When the aging time is at least 25 minutes, the aggregation concentration of the drug or drug intermediate can be further adjusted, for example, a single crystal can be prepared. However, the aging time should not be too long. The excessively long aging time may make the known single crystal further into a polycrystalline structure.

According to the embodiments of the present invention, the aging process may use any refrigeration device or any low temperature to keep the drug or drug intermediate solution in a frozen state; for example, natural cooling, compression refrigeration equipment, semiconductor refrigeration equipment, or Liquid nitrogen, liquid helium, liquid carbon dioxide, liquid oxygen, liquid ethane, dry ice, ice, etc. one or a combination of several methods.

According to an embodiment of the present invention, in step (a3), the separation may be physical and / or chemical separation of the frozen solid solvent from the system. The single crystal or amorphous material has been prepared after freezing or optional further aging. At this time, the single crystal or amorphous material is present at the interface of the solvent crystal, which needs to be separated by an appropriate method; or the solvent Remove.

According to an embodiment of the present invention, the physical means include but are not limited to one or a combination of one of quench separation, sublimation (such as vacuum sublimation), and dissolution. The sublimation can be performed by freeze-drying, for example; the vacuum sublimation can be performed by freeze-drying under vacuum conditions; and the dissolving, for example, can use another liquid solvent to dissolve the frozen solvent.

According to an embodiment of the present invention, the chemical means include, but are not limited to, one or a combination of chemical reactions and electrolysis.

According to the present invention, the method further includes the following steps:

(a4) The single crystal or amorphous prepared in step (a3).

According to an embodiment of the present invention, in step (a4), 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 .

[Method of cultivating single crystal]

As mentioned above, the present invention also provides a method for cultivating a single crystal, which includes the above-mentioned method for preparing a single crystal.

According to an embodiment of the present invention, the method for cultivating a single crystal further includes the following steps:

(b1) Transfer the single crystal of the drug or drug intermediate prepared above to the mother liquid of the drug or drug intermediate for cultivation;

(b2) Collect the single crystal of step (b1).

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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, and may be, for example, a saturated solution system, a supersaturated solution system, or an unsaturated solution. System; for example, when the substance to be crystallized is chloramphenicol; an aqueous solution of chloramphenicol is used as the mother liquor.

The preparation method of the present invention will be described in further detail below with reference to specific examples. It should be understood that the following embodiments are merely illustrative and explanations of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered by the scope of protection of the present invention.

Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the reagents and materials used in the following examples, unless otherwise specified, can be obtained from commercial sources.

The aging time described in the following examples refers to the time required to increase the temperature to the aging temperature after the freezing process is completed, and the time maintained at the aging temperature; the maintenance time refers to the time maintained at the aging temperature.

Example 1

Prepare a chloramphenicol solution with a concentration of 1 mM in water, take a 1 mL solution with a syringe, spread it on a silicon wafer, place it in a -24 ° C refrigerator to slowly cool down to complete freezing, and finally place it in a -10 ° C refrigerator for 20 minutes (The rate of temperature increase is less than 10 ° C / min), then freeze-dry the sample and completely sublimate the solid water (ice) to obtain a single crystal of chloramphenicol. Finally, select a single crystal of better quality from the beaker (the selection method is a routine choice for those skilled in the art, for example, to judge by morphology and structure), move to a saturated aqueous solution of chloramphenicol, and place it at a temperature of 25 ℃, relative humidity For a period of 40% in a constant temperature and humidity environment, a larger volume of chloramphenicol single crystal can be grown, see Figure 1.

Example 2

Prepare a chloramphenicol solution with a concentration of 10 mM in water, use a graduated cylinder to take 100 mL of the solution into a beaker, place it in a -24 ° C refrigerator to slowly cool it to complete freezing, and finally place it in a -10 ° C refrigerator for 30 minutes, followed by Single crystal can be obtained by quickly removing frozen ice in cold. Finally, select a single crystal of better quality from the silicon wafer and move it to a saturated aqueous solution of chloramphenicol. Put it in a constant temperature and constant humidity environment at a temperature of 25 ° C and a relative humidity of 40% for a period of time to grow a larger volume of chlorine. Single crystal.

Example 3

Prepare a 20 mM chloramphenicol solution with water, use a pipette to take 20 μL of the solution, and drop it to a silicon wafer of -90 ° C. The temperature of the silicon wafer is controlled by a hot and cold stage, and then the heating rate is 8 ° C / min. , Rose to -8 ℃, maintained at this temperature for 20min. Subsequently, the frozen ice was removed by quenching to obtain chloramphenicol single crystal. The single crystal with better quality was selected from the silicon wafer and transferred to a saturated aqueous solution of chloramphenicol. In the next period of time, a larger single crystal of chloramphenicol will grow.

Example 4

Prepare a 1 mM penicillin G sodium salt solution with water, take a 100 mL solution into a beaker with a graduated cylinder, place it in a -24 ° C refrigerator and slowly cool it to complete freezing, and finally place it in a -20 ° C refrigerator for 90 minutes, and then By freeze-drying the sample and sublimating the ice completely, a single crystal can be obtained. Finally, select a single crystal of better quality from the beaker and move it to a saturated aqueous solution of penicillin G sodium salt, and place it in a constant temperature and humidity environment at a temperature of 25 ° C and a relative humidity of 40% for a period of time to grow a larger volume of penicillin. G sodium salt single crystal, see Figure 2.

Example 5

Prepare a penicillin G sodium salt solution with a concentration of 100 μM in water, take a 15 μL solution with a pipette gun, and drop it to a silicon wafer of -90 ° C. The temperature of the silicon wafer is controlled by a hot and cold stage, and then the temperature is increased by 10 ° C / min The rate is increased to -10 ° C and maintained at this temperature for 30 minutes. Then freeze-dry the sample, completely sublimate the solid ice, and then select a single crystal of better quality from the silicon wafer to the saturated penicillin G sodium salt solution and place it in a constant temperature and humidity environment with a temperature of 25 ° C and a relative humidity of 40%. Over time, a larger single crystal of penicillin G sodium salt can grow.

Example 6

Prepare a baicalin solution with a concentration of 1 mM with dimethyl sulfoxide, take a 15 μL solution with a pipette gun, and drop it to a silicon wafer of -90 ° C. The temperature of the silicon wafer is controlled by a hot and cold stage, and then at 10 ° C / min heating rate, rose to -18 ℃, maintained at this temperature for 40min. Then freeze-dry the sample, completely sublimate the solid dimethyl sulfoxide, and then select a good quality single crystal from the silicon wafer and move it to a saturated baicalin solution, put it at a constant temperature of 25 ° C and a relative humidity of 40%. In a wet environment for a period of time, a larger single crystal of baicalin can grow, as shown in Figure 10.

Examples 7-35

The operation steps are the same as those in Embodiment 1, and the differences are as follows:

Example 36

Prepare a 5 μM paclitaxel solution with dimethyl sulfoxide-water with a mass ratio of 1:99. Take 5 parts of 5mL solution into a beaker with a graduated cylinder and place it in liquid nitrogen at -196 ° C to cool to completion Freeze, then slowly raise the temperature at 5 ° C / min and place them in temperature-controlled cold traps at -53 ° C, -42 ° C, -34 ° C, -30 ° C, and -23 ° C for 45 minutes, and then freeze-dry the sample to completely sublimate With a solid solvent, paclitaxel single crystal nanoparticles can be obtained, and the particle size can be continuously adjusted from 10 nm to 1500 nm. As shown in FIG. 35, as the curing temperature increases, the prepared paclitaxel single crystal nanoparticles increase. Finally, use 0.1mg / mL Tween-80 solution 1000mL to collect the obtained paclitaxel single crystal nanoparticles to form a stable suspension. The test results are shown in Figure 36. As can be seen from Figure 36, the paclitaxel monohydrate prepared from left to right The distribution of crystalline nanoparticles is 12nm, 120nm, 430nm, 680nm, 1200nm.

Example 37

Prepare a paclitaxel solution with a concentration of 3 μM with dimethyl sulfoxide-water with a mass ratio of 1:99, take a 100 μL solution with a syringe, spread it on a silicon wafer, and place it on a cold table at -80 ° C to cool down and freeze to completion After freezing, the temperature of the cold stage is raised to -53 ° C, -34 ° C, -23 ° C and maintained for 10 minutes at 20 ° C / min, and then the sample is freeze-dried and the solid solvent is completely sublimated to obtain paclitaxel amorphous nanoparticles The size is continuously adjustable from 7nm to 1000nm. As shown in Figure 37, as the curing temperature increases, the prepared amorphous nanoparticles of paclitaxel increase. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to separately collect the obtained paclitaxel amorphous nanoparticles to form a stable suspension. The test results are shown in FIG. 38. As can be seen from FIG. 38, the paclitaxel prepared from left to right has no The diameters of the shaped nanoparticles are 7 nm, 130 nm, and 910 nm, respectively.

Example 38

Use water as a solvent to prepare a paclitaxel solution with a concentration of 1 μM. Take a 1 mL solution with a syringe, spread it on a silicon wafer, and place it at -196 ° C. Liquid nitrogen is cooled and frozen to complete freezing. The temperature of the cold stage is controlled at 5 ° C / min To -45 ℃, -25 ℃, -15 ℃, -10 ℃, -5 ℃ and maintained for 45min, then freeze-dry the sample, completely sublime the solid solvent, you can get paclitaxel single crystal nanoparticles, and the particle size is 10nm to 1500nm is continuously adjustable, as shown in Figure 39, as the curing temperature increases, the prepared paclitaxel single crystal nanoparticles increase. Finally, a 0.1 mg / mL Tween-80 solution and 1000 mL were used to separately collect the obtained paclitaxel single crystal nanoparticles to form a stable suspension. The detection results are shown in FIG. 40. As can be seen from FIG. 40, the paclitaxel mono preparations prepared from left to right The particle diameters of the crystalline nanoparticles are 10 nm, 120 nm, 340 nm, 790 nm, and 1300 nm, respectively.

Example 39

Use water as a solvent to prepare a paclitaxel solution with a concentration of 1 μM, take a 0.5 mL solution with a syringe, spread it on a silicon wafer, and place it at -196 ° C in liquid nitrogen to freeze and freeze to complete freezing. The temperature of the cold stage is controlled at 20 ° C / min. Raise to -45 ℃, -15 ℃, -5 ℃ and maintain for 12min, then freeze-dry the sample, completely sublimate the solid solvent, you can get paclitaxel amorphous nanoparticles, and the particle size can be continuously adjusted from 7nm to 1000nm, as shown in the figure As shown in 41, as the aging temperature increases, the prepared amorphous nanoparticles of paclitaxel increase. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the obtained paclitaxel amorphous nanoparticles to form a stable suspension. The test results are shown in Figure 42. As can be seen from Figure 42, the paclitaxel prepared from left to right has no The diameters of the shaped nanoparticles are 6.4nm, 106nm, and 840nm, respectively.

Example 40

Prepare a 5 mM paclitaxel solution with chloroform, use a syringe to take 100 μL of the solution, spread it on a silicon wafer, place it in -196 ° C liquid nitrogen to cool down to complete freezing, then raise the temperature at 5 ° C / min and separate them The temperature was raised to -120 ℃, -109 ℃, -95 ℃, -88 ℃, -82 ℃, and cooked for 55min in a temperature-controlled cold trap, then the sample was freeze-dried, and the solidified solvent was completely sublimated to obtain paclitaxel single crystal nanoparticles. And the particle size is continuously adjustable from 10nm to 1500nm. Specifically, the particle diameters of the prepared paclitaxel single crystal nanoparticles are 13nm, 150nm, 390nm, 770nm, and 1180nm, respectively, indicating that the prepared paclitaxel increases with the aging temperature. With the increase of single crystal nanoparticles. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to separately collect the obtained paclitaxel single crystal nanoparticles to form a stable suspension.

In addition, 50 μL of the above paclitaxel solution was spread on a silicon wafer cooled to -150 ° C, and then heated to a temperature controlled cooling stage of -120 ° C, -95 ° C, and -82 ° C at a heating rate of 25 ° C / min, respectively. Maintain for 15 minutes, then freeze-dry the sample and completely sublimate the solid solvent to obtain amorphous paclitaxel nanoparticles, and the particle size can be continuously adjusted from 7nm to 1000nm. The particle size of the prepared paclitaxel amorphous nanoparticles is 9.5nm. , 320nm, 900nm, indicating that as the aging temperature increases, the prepared amorphous nanoparticles of paclitaxel increase accordingly. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to collect the obtained paclitaxel amorphous nanoparticles to form a stable suspension.

Example 41

Prepare a 1 mM paclitaxel solution with acetonitrile, use a pipette to take 10 μL of the solution, drop it on a silicon wafer that has been cooled to -196 ° C, then raise the temperature at 5 ° C / min, and place it in- The surface of the cold table at 83 ° C is maintained for 30 minutes, the surface of the cold table at -78 ° C for 45 minutes, the surface of the cold table at -65 ° C for 55 minutes, the surface of the cold table at -57 ° C for 65 minutes, and the surface of the cold table at -48 ° C After maintaining for 75 minutes, the sample was freeze-dried and the solidified solvent was completely sublimated to obtain paclitaxel single crystal nanoparticles with a particle size continuously adjustable from 10 nm to 1500 nm. The particle size of the prepared paclitaxel single crystal nanoparticles was 11.8 nm, 140nm, 410nm, 830nm, and 1200nm indicate that as the curing temperature increases, the prepared paclitaxel single crystal nanoparticles increase. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to separately collect the obtained paclitaxel single crystal nanoparticles to form a stable suspension.

In addition, 20 μL of the above-mentioned paclitaxel solution was spread on a silicon wafer cooled to -150 ° C, and then heated to -83 ° C, -65 ° C, -48 ° C for 10 minutes at a temperature increase rate of 25 ° C / min, and then frozen After drying the sample and completely sublimating the solid solvent, amorphous paclitaxel nanoparticles can be obtained and the particle size can be continuously adjusted from 7nm to 1000nm. The particle diameters of the prepared paclitaxel amorphous nanoparticles are 78.2nm, 300nm, and 935nm, respectively. As the aging temperature increases, the prepared amorphous nanoparticles of paclitaxel increase. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to collect the obtained paclitaxel amorphous nanoparticles to form a stable suspension.

Example 42

Prepare a 10-hydroxycamptothecin solution with a concentration of 5 μM with dimethyl sulfoxide. Take 5 5 mL solutions of each in a graduated cylinder and place them in a beaker. Place them in liquid nitrogen at -196 ° C to cool to complete freezing, and then Slowly heat up at 8 ° C / min and place them in -50 ° C, -45 ° C, -40 ° C, -35 ° C, -25 ° C temperature-controlled cold traps for 40 minutes, and then freeze-dry the samples to completely sublime solid dimethyl Sulfoxide, 10-hydroxycamptothecin single crystal nanoparticles can be obtained, and the average size of the particles is continuously adjustable from 10nm to 1000nm. The test results are shown in Figure 43. From Figure 43, it can be seen that the prepared 10- The average particle diameters of the hydroxycamptothecin single crystal nanoparticles are 10.7nm, 130nm, 420nm, 650nm, and 1190nm, respectively. Finally, the obtained 10-hydroxycamptothecin single crystal nanoparticles were collected with 1000 mg of 0.1 mg / mL Tween-80 solution to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 44.

In addition, spread the above 5 μM 10-hydroxycamptothecin solution on a silicon wafer cooled to -90 ° C, and then raise it to -50 ° C, -40 ° C, -25 ° C at a temperature increase rate of 25 ° C / min After aging for 15 minutes, the sample was freeze-dried and the solid dimethyl sulfoxide was completely sublimated to obtain 10-hydroxycamptothecin amorphous nanoparticles with adjustable sizes. The test results are shown in Figure 45, which can be seen from Figure 45. The prepared 10-hydroxycamptothecin amorphous nanoparticles have a particle size of 7.8 nm, 200 nm, and 970 nm, respectively. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the amorphous nanoparticles to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 46.

Example 43

Prepare a solution of 5-hydroxycamptothecin at a concentration of 5mM with a mixed solvent of 95wt% chloroform and 5wt% methanol, take a 100μL solution with a syringe, spread it on a silicon wafer, and place it at -196 ° C in liquid nitrogen to cool down to complete Freeze, then slowly raise the temperature at 5 ° C / min and place them in -100 ° C, -96 ° C, -88 ° C, -85 ° C, -79 ° C temperature-controlled cold traps for 45 minutes, and then freeze-dry the samples to completely sublimate With a solid solvent, 10-hydroxycamptothecin single crystal nanoparticles can be obtained, and the average size of the particles is 12 nm, 105 nm, 440 nm, 680 nm, and 1200 nm, respectively. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to collect the obtained single crystal nanoparticles to form a stable suspension.

In addition, 50 μL of the above 5 mM 10-hydroxycamptothecin solution was spread on a silicon wafer cooled to -150 ° C, and then heated to -100 ° C, -88 ° C, -79 at a temperature increase rate of 25 ° C / min After aging at ℃ for 20min, the sample was freeze-dried and the solid solvent was completely sublimated to obtain 10-hydroxycamptothecin amorphous nanoparticles with adjustable sizes, the average sizes of which were 8.8nm, 93nm, 380nm, 550nm and 910nm. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to separately collect the obtained amorphous nanoparticles to form a stable suspension.

Example 44

Prepare a solution of 10-hydroxycamptothecin at a concentration of 1 mM with a mixed solvent of 2% by weight of dimethyl sulfoxide and 98% by weight of water, take a 10 μL solution with a pipette gun, and drop it on a silicon wafer that has been cooled to -196 ° C Then, slowly raise the temperature at 6 ° C / min and raise the temperature to -60 ° C for 45 minutes, 30 minutes at -52 ° C for 30 minutes, and -43 ° C for 35 minutes. The surface of the cold stage at 38 ° C was cured for 48 minutes and the surface of the cold stage at -27 ° C for 51 minutes, and then the sample was freeze-dried to completely sublimate the solidified solvent to obtain 10-hydroxycamptothecin single crystal nanoparticles with average particle sizes. It is 11.5nm, 125nm, 480nm, 720nm, 1150nm. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to collect the obtained single crystal nanoparticles to form a stable suspension.

In addition, 10 μL of the above 10-hydroxycamptothecin solution was spread on a silicon wafer cooled to -90 ° C, and then heated to -60 ° C, -43 ° C, and -27 ° C at a heating rate of 30 ° C / min. After aging for 13 minutes, and then freeze-drying the sample, completely sublimating the solid solvent, 10-hydroxycamptothecin amorphous nanoparticles with adjustable sizes can be obtained, and their average particle sizes are 7.5nm, 101nm, 420nm, 650nm, and 980nm, respectively. Finally, 1000 mg of 0.1 mg / mL Span-80 solution was used to separately collect the obtained amorphous nanoparticles to form a stable suspension.

Example 45

Prepare a camptothecin solution with a concentration of 3mM with 95wt% methanol-5wt% acetonitrile. Take four 15μL solutions and freeze them completely on the surface of a silicon wafer cooled to -150 ℃. The temperature is controlled at 5 ℃ / min. Slowly increase the temperature to -121 ℃, -100 ℃, -94 ℃, -86 ℃, aging for 50min, and then freeze-dry the sample to completely sublime the solid solvent to obtain camptothecin single crystal nanoparticles with an average particle size of 10nm It can be continuously adjusted up to 1000nm. The detection results are shown in Figure 47. From Figure 47, it can be seen that the average particle diameters of the prepared camptothecin single crystal nanoparticles are 10.2nm, 250nm, 490nm, and 1120nm, respectively. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the obtained camptothecin single crystal nanoparticles to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 48.

In addition, the above 3mM camptothecin solution was spread on a silicon wafer cooled to -150 ° C, and then heated to -121 ° C, -100 ° C, -86 ° C, and aging for 15min at a temperature increase rate of 25 ° C / min. Then, freeze-dry the sample and completely sublimate the solid solvent to obtain camptothecin amorphous nanoparticles with adjustable size. The test results are shown in Figure 49. As can be seen from Figure 49, the prepared camptothecin amorphous nanoparticles The average particle size of 7.8nm, 200nm, 970nm. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the amorphous nanoparticles to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 50.

Example 46

Prepare a 50 μM irinotecan solution with 5 wt% dimethyl sulfoxide and 95 wt% water. Take 4 10 μL solutions and place them on the surface of a silicon wafer cooled to -80 ℃ to completely freeze them. / min Slowly increase the temperature to -50 ° C, -35 ° C, -28 ° C, -21 ° C, aging for 50 minutes, then freeze-dry the sample and completely sublimate the solid solvent to obtain irinotecan single crystal nanoparticles, and the average particle size The size is continuously adjustable from 10nm to 1000nm. The detection results are shown in Fig. 51. It can be seen from Fig. 51 that the average particle size of the prepared irinotecan single crystal nanoparticles is 12nm, 240nm, 460nm, and 1000nm, respectively. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the irinotecan single crystal nanoparticles to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 52.

In addition, the above 50 μM irinotecan solution was spread on a silicon wafer cooled to -80 ° C, and then it was heated to -50 ° C, -35 ° C, -21 ° C at 15 ° C / min heating rate for 15 minutes. Then, freeze-dry the sample and completely sublimate the solid solvent to obtain irinotecan amorphous nanoparticles with adjustable size. The test results are shown in Figure 53. As can be seen from Figure 53, the prepared irinotecan amorphous nanoparticles The average particle diameters are 9.9nm, 220nm and 940nm. Finally, the amorphous nanoparticles obtained by using 0.1mg / mL Tween-80 solution 1000mL were collected to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 54.

Example 47

A gefitinib solution with a concentration of 5 mM was prepared with dimethyl sulfoxide, and four 20 μL solutions were separately placed on the surface of a silicon wafer cooled to -50 ° C to completely freeze, and the temperature controlled cold stage was slowly heated up at 5 ° C / min. To -42 ℃, -27 ℃, -22 ℃, -16 ℃, aging for 50min, and then freeze-dry the sample, completely sublimate the solid solvent, you can get gefitinib single crystal nanoparticles, and the average particle size is 10nm to 1000nm is continuously adjustable. The detection results are shown in Figure 55. It can be seen from Figure 55 that the average particle size of the prepared gefitinib single crystal nanoparticles is 9.7nm, 280nm, 465nm, and 1115nm, respectively. Finally, the collected gefitinib single crystal nanoparticles were collected with 1000 mg of 0.1 mg / mL Tween-80 solution to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 56.

In addition, the above 5mM gefitinib solution was spread on a silicon wafer cooled to -50 ° C, and then heated to -42 ° C, -27 ° C, -16 ° C at 25 ° C / min heating rate, and cured After 15 minutes, the sample was freeze-dried and the solid solvent was completely sublimated to obtain gefitinib amorphous nanoparticles with adjustable size. The test results are shown in Figure 57. As can be seen from Figure 57, the prepared gefitinib has no The average particle size of the shaped nanoparticles is 5.6 nm, 230 nm, and 870 nm, respectively. Finally, 1000 mg of 0.1 mg / mL Tween-80 solution was used to collect the amorphous nanoparticles to form a stable suspension, and the particle size distribution was tested. The test results are shown in Figure 58.

In the above, the embodiment of the present invention has been described. However, the present invention is not limited to the above-mentioned embodiment. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A method for preparing a single crystal or an amorphous substance of a drug or a drug intermediate, the method includes the following steps:

   (a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

   (a2) freezing the solution of the drug or drug intermediate in step (a1) and optionally aging to prepare a mixed system of a frozen solvent containing a single crystal or amorphous substance of the drug or drug intermediate; optionally ,

   (a3) Separate the single crystal or amorphous substance of the drug or drug intermediate from the mixed system of step (a2).
2. The method according to claim 1, wherein the method comprises the following steps:

   (a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

   (a2) freezing the solution of the drug or drug intermediate in step (a1) and optionally aging to prepare a mixed system of a frozen solvent containing a single crystal of the drug or drug intermediate; optionally,

   (a3) separating the single crystal of the drug or drug intermediate from the mixed system of step (a2);

   Wherein, 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.

   Preferably, during the aging process, 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-crystal frozen solvent containing the drug or drug intermediate.

   Preferably, during the curing process, the temperature is increased to a certain temperature at an arbitrary heating or cooling rate for at least 25 minutes to obtain a mixed system of a single-crystal frozen solvent containing a drug or a drug intermediate.

   Preferably, during the curing process, the temperature is increased to a certain temperature at a temperature increase or decrease rate of less than 10 ° C./min, and the curing is performed for at least 25 minutes to obtain a mixed system of a single-crystal frozen solvent containing a drug or a drug intermediate.
3. The method according to claim 1, wherein the method comprises the following steps:

   (a1) formulating a solution of a drug or a drug intermediate, wherein the solvent for preparing the solution is a freezeable solvent;

   (a2) freezing and aging the solution of the drug or drug intermediate in step (a1) to prepare a mixed system of an amorphous frozen solvent containing the drug or drug intermediate; optionally,

   (a3) Separate the amorphous form of the drug or drug intermediate from the mixed system of step (a2);

   Wherein, 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.
4. The method according to any one of claims 1 to 3, characterized in that, by controlling the curing temperature, a single crystal or an amorphous substance of a drug or a drug intermediate with adjustable particle size can also be prepared, that is, the isolated drug or The particle size of the single crystal or amorphous of the drug intermediate increases with the increase of the curing temperature.

   Preferably, the drugs include natural drugs (such as plant drugs, antibiotics, biochemical drugs, etc.), synthetic drugs or genetically engineered drugs.

   Preferably, the medicine includes medicine for human body, including but not limited to: antibiotic medicine, cardiovascular medicine, digestive system medicine, respiratory system medicine, urinary system medicine, blood system medicine, facial medicine medicine, anti-rheumatic medicine Drugs, diabetes drugs, hormone drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins, etc.

   Preferably, the medicine also includes medicines for animals and plants, including but not limited to: antimicrobial medicines, antiparasitic medicines, disinfection and antiseptic medicines, medicines acting on the central nervous system, medicines acting on the plant nervous system, anesthesia Medicines and their auxiliary drugs, corticosteroid drugs, digestive system drugs, respiratory system drugs, urinary system drugs, circulatory system drugs, reproductive system drugs, blood and hematopoietic system disease drugs, vitamins and minerals, regulating water, Electrolytes and acid-base balance drugs, antidote and anti-allergic drugs, topical drugs and pharmaceutical excipients, probiotics, plant growth regulators, insecticides, fungicides, etc.

   Preferably, the pharmaceutical intermediate refers to a compound that can prepare the above-mentioned drugs; including a compound that prepares antibiotic drugs, a compound that prepares cardiovascular and cerebrovascular drugs, a compound that prepares drugs for the digestive system, a compound that prepares drugs for the respiratory system, and a preparation for the urinary system Compounds for drugs, compounds for preparing blood system drugs, compounds for preparing facial medicine, compounds for preparing anti-rheumatic drugs, compounds for preparing diabetes drugs, compounds for preparing hormone drugs, compounds for preparing dermatological drugs, compounds for preparing gynecological drugs Compounds, compounds for preparing antitumor drugs, compounds for preparing antipsychotic drugs, compounds for preparing nervous system drugs, compounds for preparing vitamins, etc .;

   Preferably, the drug or drug intermediate may be a hydrophilic drug or a hydrophobic drug;

   Preferably, the drug or drug intermediate is selected from at least one of the following substances: paclitaxel, myritinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib , Sirolimus, aprepitant, fenofibrate, nepafenac, dantrolene sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol, the drug or the drug The intermediate is selected from at least one of the following substances: chloramphenicol, penicillin G sodium salt, baicalin, carbenicillin disodium salt, nafcillin sodium monohydrate, ginsenoside Rh ₂ , ginsenoside Rd, Ginsenoside Rb ₂ , gibberellin A ₁ , gibberellin A ₅ , baicalin, baicalein, β-sitosterol, brassicasterol, jasmonic acid, p-toluenesulfonic acid.
5. The method according to any one of claims 1 to 4, wherein in step (a1), the freezeable solvent includes but is not limited to water and / or organic solvent.

   Preferably, in step (a1), the solubility of the drug or drug intermediate in the solvent is easily soluble, soluble, slightly soluble or poorly soluble.

   Preferably, the amount of the drug or drug intermediate dissolved in the solvent is greater than or equal to 1 × 10 ^-7 g / 100g (used solvent), for example greater than or equal to 0.001g / 100g (used solvent), such as greater than or equal to 0.01g / 100g (solvent used), such as greater than or equal to 0.1g / 100g (solvent used), such as greater than or equal to 1g / 100g (solvent used), such as greater than or equal to 10g / 100g (solvent used).

   Preferably, the step (a2) specifically includes the following steps:

   The solution of the drug or drug intermediate in step (a1) is cooled and frozen into a solid mixture, and optionally subjected to aging treatment to prepare a mixed system of a frozen solvent containing a single crystal or an amorphous substance of the drug or drug intermediate;

   Preferably, the freezing is to convert the solution of the drug or drug intermediate in step (a1) from a liquid state to a solid state.
6. The method according to any one of claims 1 to 5, wherein the freezing method includes, but is not limited to, natural cooling freezing, compression refrigeration equipment cooling freezing, semiconductor refrigeration equipment cooling freezing, liquid nitrogen cooling freezing, liquid helium Cooling and freezing, liquid carbon dioxide cooling and freezing, liquid oxygen cooling and freezing, liquid ethane cooling and freezing, dry ice cooling and freezing, ice cooling and freezing, one or a combination of several cooling methods;

   Preferably, 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;

   Preferably, the freezing includes but is not limited to complete freezing and incomplete freezing;

   Preferably, the aging process is that the solution of the drug or drug intermediate stays in a frozen state for a period of time.
7. The method according to any one of claims 1 to 6, characterized in that, in step (a3), the separation is to separate the solvent frozen into a solid from the mixed system by physical and / or chemical means;

   Preferably, the physical methods include but are not limited to one or a combination of several methods of quenching separation, sublimation (such as vacuum sublimation), and dissolution;

   Preferably, the chemical method includes but is not limited to one or a combination of several methods in chemical reaction and electrolysis.
8. The method according to any one of claims 1-7, wherein the method further comprises the following steps:

   (a4) The single crystal or amorphous prepared in the collection step (a3);

   Preferably, in step (a4), 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.
9. A method for cultivating a single crystal of a drug or a drug intermediate, characterized in that the method includes the method for preparing a single crystal according to any one of claims 1-8;

   Preferably, the method for culturing a single crystal of a drug or a drug intermediate further includes the following steps:

   (b1) Transfer the single crystal of the drug or drug intermediate prepared above to the mother liquid of the drug or drug intermediate for cultivation;

   (b2) Collect the single crystal of step (b1).
10. The method according to claim 9, wherein in step (b1), the transferring may be transferring the mixed system of the single crystal containing the drug or drug intermediate and the frozen solvent in step (a2) to Single crystal culture in the mother liquid of the drug or drug intermediate; or the transfer is to directly transfer the single crystal after removing the solvent in step (a3) to the mother liquid of the drug or drug intermediate for single crystal culture; or The single crystal collected in step (a4) is transferred to the mother liquor of the drug or drug intermediate for single crystal culture;

    Preferably, 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;

    Preferably, in step (b1), 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.

    Preferably, in step (b2), 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.

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