CN110607554B - Method for preparing medicine or medicine intermediate monocrystal or amorphous substance - Google Patents
Method for preparing medicine or medicine intermediate monocrystal or amorphous substance Download PDFInfo
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- CN110607554B CN110607554B CN201911039683.0A CN201911039683A CN110607554B CN 110607554 B CN110607554 B CN 110607554B CN 201911039683 A CN201911039683 A CN 201911039683A CN 110607554 B CN110607554 B CN 110607554B
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- single crystal
- medicine
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- 239000003960 organic solvent Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 20
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/08—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by cooling of the solution
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention relates to the technical field of single crystal preparation, in particular to a method for preparing a single crystal or amorphous substance of a medicament or a medicament intermediate. The method uses solution freezing to induce nucleation and crystallization of the medicine or the medicine intermediate, and realizes crystallization of the dissolved medicine or the medicine intermediate in the freezing process of the solution, thereby rapidly and effectively preparing single crystals or amorphous substances of the medicine or the medicine intermediate. Meanwhile, the preparation problem of single crystals or amorphous substances of molecules which are difficult to crystallize in the traditional medicine or medicine intermediate single crystal culture is solved. The method realizes the acquisition of the single crystal or amorphous substance of the medicine or the medicine intermediate under extremely low solution concentration for the first time; and also solves the problems of difficult control, easy formation of polycrystal, twin crystal and the like of single crystal formation caused by too fast aggregation of medicines or medicine intermediates under high concentration. The method has wide application range and is applicable to the existing medicines or medicine intermediates.
Description
The present application claims the priority of the prior application filed on 10 and 30 days 2018 to the national intellectual property agency of China, having the patent application number 2018112806394, entitled "method for preparing and growing single crystals of a drug or drug intermediate", which is incorporated herein by reference in its entirety.
Technical Field
The invention relates to the technical field of preparation of single crystals or amorphous substances, in particular to a method for inducing crystallization of a drug or a drug intermediate or forming an amorphous substance by utilizing solution freezing, which is applicable to preparation of single crystals or amorphous substances of any drug or drug intermediate which can be dissolved in a solvent.
Background
The medicine, whether natural medicine (such as plant medicine, antibiotic, biochemical medicine, etc.), synthetic medicine or genetic engineering medicine, is some chemical composed of chemical elements such as C, H, O, N, S in terms of its chemical nature. However, drugs are not just general chemicals, but are special chemicals that organisms use to prevent, treat, diagnose diseases, or to regulate organism function, improve quality of life, and maintain organism health.
The pharmaceutical intermediates generally refer to those key raw materials specifically used for the production of pharmaceuticals, such as key intermediates 6-APA (6-aminopenicillanic acid), 7-ACA (7-aminocephalosporanic acid) and 7-ADCA (7-aminodesacetoxy cephalosporanic acid) for the production of cephalosporins, various cephalosporin side chains, piperazine and derivatives thereof used for the production of quinolones, and the like, and do not include those basic chemical raw materials used for the production of pharmaceuticals, such as ethanol, acetic acid, and the like.
At present, methods for crystallizing drugs or drug intermediates are widely studied, and common methods include a slow solvent volatilization method, a cooling method, a liquid phase diffusion method, a gas phase diffusion method and the like. However, the method generally has the problems of poor crystal nucleation and growth controllability, easy generation of polycrystal or twin crystal and the like. It is well known in the art that high purity drugs or drug intermediates are critical to improving the quality of life in humans. Therefore, how to efficiently prepare perfect medicines or medicine intermediate single crystals has important significance for industrial production and basic research. In addition, the amorphous medicine or the amorphous medicine intermediate can be better absorbed by human body, and has important significance for the production of medicine industry and basic research.
Disclosure of Invention
In view of the deficiencies of the prior art in the preparation of single crystals or amorphous forms of a drug or drug intermediate, the present invention aims to provide a method for preparing single crystals or amorphous forms of a drug or drug intermediate by controlling the feed and aggregation rate of a drug or drug intermediate by freezing and optionally maturation of a drug or drug intermediate solution; the invention realizes the controllable preparation of the monocrystal or amorphous substance of the medicine or the medicine intermediate by freezing the solution for the first time, namely, realizes the regulation and control of the supply rate and the aggregation rate of the medicine or the medicine intermediate (namely, the medicine or the medicine intermediate) by controlling the freezing and optional curing process of the medicine or the medicine intermediate solution, thereby regulating and controlling whether the medicine or the medicine intermediate can nucleate crystallization and the crystal growth condition thereof, and realizing the efficient preparation of the monocrystal or amorphous substance of the medicine or the medicine intermediate.
The invention aims at realizing the following technical scheme:
a method of preparing a single crystal or amorphous form of a drug or drug intermediate, the method comprising the steps of:
(a1) Preparing a solution of a drug or drug intermediate, wherein the solvent from which the solution is prepared is a freezable solvent;
(a2) Freezing, optionally curing, the solution of the drug or drug intermediate of step (a 1) to produce a mixed system comprising single crystals or amorphous material of the drug or drug intermediate and the frozen solvent; optionally, the composition may be used in combination with,
(a3) Separating the single crystal or amorphous form of the drug or drug intermediate from the mixed system of step (a 2).
In the present invention, the freezable solvent refers to a solvent that can form a solid state 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 medicaments include medicaments for the human body including, but not limited to: antibiotic drugs, cardiovascular and cerebrovascular drugs, digestive system drugs, respiratory system drugs, urinary system drugs, blood system drugs, five sense organs drugs, antirheumatic drugs, diabetes drugs, hormonal drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins, etc.
The medicaments also include medicaments for animals and plants, including but not limited to: antimicrobial agents, antiparasitic agents, antiseptic agents, agents acting on the central nervous system, agents acting on the autonomic nervous system, narcotics and their auxiliary agents, corticosteroids, digestive system agents, respiratory system agents, urinary system agents, circulatory system agents, reproductive system agents, blood and hematopoietic system disease agents, vitamins and minerals, agents regulating water, electrolytes, acid-base balance, antidotes and antiallergic agents, topical agents and pharmaceutical excipients, probiotics, plant growth regulators, pesticides, bactericides, and the like.
The drug intermediate refers to a compound capable of preparing the drug. Including antibiotic-type medicine preparation, cardiovascular-cerebrovascular-type medicine preparation, digestive-type medicine preparation, respiratory-type medicine preparation, urinary-type medicine preparation, blood-type medicine preparation, five-sense organ-type medicine preparation, antirheumatic-type medicine preparation, diabetes-type medicine preparation, hormone-type medicine preparation, dermatological-type medicine preparation, gynecological-type medicine preparation, antitumor-type medicine preparation, antipsychotic-type medicine preparation, nervous-type medicine preparation, vitamin-type medicine preparation, etc.
In the present invention, the drug or drug intermediate is soluble, slightly soluble or poorly soluble in a solvent.
In the present invention, the step (a 2) specifically includes the following steps:
cooling and freezing the solution of the medicine or the medicine intermediate in the step (a 1) into a solid mixture, and optionally curing to prepare the mixed system.
In step (a 2) of the present invention, the freezing is to convert the solution of the drug or drug intermediate of step (a 1) from a liquid state to a solid state.
In the invention, the freezing method comprises one or a combination of several cooling freezing methods of natural cooling freezing, cooling freezing of compression refrigerating equipment, cooling freezing of semiconductor refrigerating equipment, cooling freezing of liquid nitrogen, cooling freezing of liquid helium, cooling freezing of liquid carbon dioxide, cooling freezing of liquid oxygen, cooling freezing of liquid ethane, cooling freezing of dry ice, cooling freezing of ice and the like.
In the invention, the freezing process comprises one or a combination of a plurality of freezing processes including rapid cooling, slow cooling, step cooling, heating first and cooling later.
In the present invention, the freezing includes, but is not limited to, complete freezing, incomplete freezing.
In the invention, the curing process is that the solution of the drug or the drug intermediate stays for a period of time under the condition of keeping the frozen state.
In the present invention, the aging time means a time required for heating to an aging temperature after the freezing process is completed, and a time required for maintaining at the aging temperature.
In one embodiment, the step (a 2) is to freeze the solution of the drug or drug intermediate of step (a 1) to prepare a mixed system of the single crystal containing the drug or drug intermediate and the frozen solvent.
In one embodiment, the step (a 2) includes a curing process, that is, the step (a 2), and the solution of the drug or the drug intermediate in the step (a 1) is frozen and cured to prepare a mixed system of the single crystal or the amorphous substance containing the drug or the drug intermediate and the frozen solvent.
In one embodiment, in the step (a 2), during the curing process, the temperature is raised or lowered at a speed of 10 ℃/min or more to a certain temperature, and the curing time is less than 25min, so as to prepare the mixed system of the amorphous substance containing the drug or the drug intermediate and the frozen solvent.
In one embodiment, the greater the difference between the temperature at which the amorphous material is obtained and the freezing temperature, the greater the particle size of the amorphous material obtained. The particle size of the obtained amorphous material can be controlled by adjusting the magnitude of the temperature difference.
In one embodiment, step (a 2) is performed by heating or cooling the temperature to a certain temperature at a rate of less than 10 ℃/min during the aging process, and/or the aging time is at least 25min, to prepare a mixed system of the single crystal containing the drug or the drug intermediate and the frozen solvent.
Illustratively, during the curing process, the temperature is allowed to reach a certain temperature at a rate of rise or fall of less than 10 ℃/min, and is maintained for a period of time to prepare a mixed system of single crystals containing the drug or drug intermediate and the frozen solvent.
Illustratively, in the curing process, the temperature is raised or lowered at any rate to a certain temperature, and the mixture is cured for at least 25min to prepare a mixed system of the single crystal containing the drug or the drug intermediate and the frozen solvent.
Illustratively, in the curing process, the temperature is raised to a certain temperature at a heating or cooling rate of less than 10 ℃/min, and is cured for at least 25min, so as to prepare a mixed system of the single crystal containing the drug or the drug intermediate and the frozen solvent.
In the present invention, in step (a 3), the separation is to separate the solvent frozen into a solid from the mixed system by physical means and/or chemical means.
In the present invention, the physical means include, but are not limited to, one or a combination of quenching separation, sublimation (e.g., vacuum sublimation), dissolution.
In the present invention, the chemical means includes, but is not limited to, one or a combination of chemical reaction and electrolysis.
In the invention, the method further comprises the following steps:
(a4) Collecting the single crystal or amorphous substance obtained in the step (a 3).
In the present invention, in step (a 4), the collection includes, but is not limited to, collection with one or a combination of several of optical microscope, scanning electron microscope, dual beam electron microscope, transmission electron microscope.
The invention also provides a method for culturing a single crystal of a drug or drug intermediate, which comprises the method for preparing the single crystal.
In the present invention, the method of growing a drug or drug intermediate single crystal further comprises the steps of:
(b1) Transferring the prepared single crystal of the medicine or the medicine intermediate into a mother solution of the medicine or the medicine intermediate for culture;
(b2) Collecting the single crystal of step (b 1).
In the present invention, in the step (b 1), the transfer may be a step of transferring the mixed system of the single crystal containing the drug or the drug intermediate and the frozen solvent of the step (a 2) into a mother liquor of the drug or the drug intermediate to perform single crystal cultivation; or the transfer may be a single crystal culture in which the single crystal after the solvent removal in step (a 3) is directly transferred to a mother liquor of a drug or drug intermediate; or transferring the single crystal collected in the step (a 4) into a mother solution of a drug or drug intermediate for single crystal cultivation.
In the present invention, the transfer includes, but is not limited to, one or a combination of several of optical microscope transfer, scanning electron microscope transfer, dual beam electron microscope transfer, and transmission electron microscope transfer.
In the present invention, in the step (b 1), the method of growing the single crystal includes, but is not limited to, one or a combination of several of evaporation, cooling, and diffusion.
In the present invention, in step (b 2), the collection includes, but is not limited to, collection with one or a combination of several of optical microscope, scanning electron microscope, dual beam electron microscope, transmission electron microscope.
Advantageous effects
1. Aiming at the defects of difficult control of molecular supply, aggregation, nucleation speed and the like in the process of preparing a medicine or medicine intermediate monocrystal or amorphous substance in the traditional method, the invention provides a method for inducing nucleation and crystallization of the medicine or medicine intermediate by freezing solution for the first time. The preparation of single crystals or amorphous forms of a drug or drug intermediate is rapid and efficient by regulating the freezing process, and optionally the maturation process, of a frozen solution of the drug or drug intermediate. Meanwhile, the method can solve the problem of difficult crystallization of molecules in the traditional single crystal preparation and culture, and can also solve the problem that some substances are difficult to form amorphous substances, in particular to form high-purity amorphous substances.
2. Compared with the traditional evaporation method or cooling crystallization method, the freezing treatment mode adopted by the invention enables the regulating and controlling range of the concentration of the solution of the medicine or the medicine intermediate to be larger, and the preparation of the medicine or the medicine intermediate monocrystal or amorphous substance can be realized from very low concentration to supersaturated concentration. The method realizes the acquisition of the medicine or medicine intermediate monocrystal or amorphous substance under extremely low solution concentration for the first time; meanwhile, the problems of difficult control of single crystal formation, easy formation of polycrystal, twin crystal and the like caused by too fast aggregation of medicines or medicine intermediates under high concentration are solved; in addition, the present invention has the advantage of obtaining single crystals or amorphous forms of the drug or drug intermediate in a short period of time (minutes to hours).
3. The solution freezing is a technical key point in the invention. The freezing process refers to freezing the solution in any manner, and the freezing time, freezing temperature gradient, freezing method, freezing process, and the like are not particularly limited. Experiments prove that the solute monocrystal or amorphous substance is prepared by freezing a solution, and the essence is that in the freezing process, the solvent is frozen into a solid state (such as water molecules form ice crystals), and simultaneously, the medicine or medicine intermediate is released and aggregated at the interface of the solvent in the solid state (such as the ice crystal interface), and the release and aggregation rate of the medicine or medicine intermediate is further regulated by regulating the crystallization process of the solvent and the recrystallization process of the crystallized solvent (such as the water crystallization process and the ice crystal recrystallization process), so that the nucleation and growth regulation of the medicine or medicine intermediate is effectively realized, and the monocrystal or amorphous substance of the target molecule is further obtained.
4. The curing process of the invention is to keep the frozen solution in a solid state or a solid-liquid mixed state for a certain time, the temperature is not limited, but the heating or cooling speed needs to be controlled. Experiments prove that the curing process can be optionally used as a complementary means to the freezing process, and can optimize the regulation and control of the recrystallization of solute crystals, thereby regulating and controlling the release rate of the drug or the drug intermediate in the crystallized solvent and the aggregation rate of the drug or the drug intermediate to the solvent interface of the crystallization, and being beneficial to further optimizing the growth of amorphous matters and/or the nucleation and growth of single crystals after the solution is frozen. Moreover, the curing process is free from excessive limitation on temperature, and the frozen system is not required to be continuously frozen, but single crystals or amorphous substances with the particle size ranging from nanometer to micrometer can be obtained through the curing process, so that the optimal preparation of the amorphous substances or single crystals can be realized at a more economical temperature with higher efficiency, the reduction of energy consumption is facilitated, and the cost is greatly saved. Compared with the traditional method, the method realizes the optimal regulation and control of the recrystallization of the crystallized solvent by regulating and controlling the temperature rising or reducing rate of the curing process, can further regulate and control the aggregation speed of the medicine or the medicine intermediate in the crystallized solvent to the interface of the crystallized solvent, further effectively obtain the single crystal or the amorphous substance of the medicine or the medicine intermediate, has the advantages of energy saving and the like, and is more beneficial to the large-scale industrial production of the amorphous substance or the single crystal of the target molecule.
5. The preparation method of amorphous substance or single crystal and the further culture method of single crystal provided by the invention have wide application range, are applicable to the existing medicines or medicine intermediates, and can be used for obtaining single crystals of substances which are difficult to crystallize in the traditional method and obtaining amorphous substances which are difficult to obtain. And the experimental method is simple and has strong operability. The method is not only applicable to basic research in laboratories, but also meets the requirements of industrial production.
6. The solvent of the invention is convenient to select, and can be either a polar solvent or a nonpolar solvent as long as the solvent can be frozen. The method provides different selection modes for dissolving different molecules, particularly for drugs or drug intermediates which are soluble in a water system, a large amount of organic solvents are omitted, the cost is reduced, and the method has the advantages of environment friendliness and the like.
Drawings
FIG. 1 is a scanning electron micrograph of chloramphenicol single crystal and its molecular formula.
FIG. 2 is a scanning electron micrograph of a single crystal of penicillin G sodium salt and its molecular formula.
FIG. 3 is a scanning electron micrograph of a single crystal of carbenicillin disodium salt and its molecular formula.
FIG. 4 is a scanning electron micrograph and molecular formula of nafcillin sodium monohydrate single crystal.
FIG. 5 is a drawing of ginsenoside Rh 2 Scanning electron microscope pictures and molecular formulas of single crystals.
FIG. 6 is a scanning electron micrograph of a single crystal of ginsenoside Rd and its molecular formula.
FIG. 7 is ginsenoside Rb 2 Scanning electron microscope pictures and molecular formulas of single crystals.
FIG. 8 is gibberellin A 1 Scanning electron microscope pictures and molecular formulas of single crystals.
FIG. 9 is gibberellin A 5 Scanning electron microscope pictures and molecular formulas of single crystals.
FIG. 10 is a scanning electron micrograph of a baicalein single crystal.
FIG. 11 is a scanning electron micrograph of baicalin single crystals.
FIG. 12 is a scanning electron micrograph of a single crystal of scutellarin.
FIG. 13 is a scanning electron micrograph of a β -sitosterol single crystal.
FIG. 14 is a scanning electron micrograph of a campesterol single crystal and its molecular formula.
FIG. 15 is a scanning electron micrograph of a jasmonic acid single crystal and molecular formula.
FIG. 16 is a scanning electron micrograph of a single crystal of p-toluenesulfonic acid.
FIG. 17 is a schematic diagram of the preparation of a single crystal of a drug or drug intermediate of the present invention.
FIG. 18 is a diagram showing a process of forming a single crystal of AIE 35.
FIG. 19 is a diagram showing a process of forming a single crystal of p-toluenesulfonic acid.
FIG. 20 is a transmission electron micrograph and molecular formula of amorphous paclitaxel nanoparticles, scale-100 nm.
FIG. 21 is a transmission electron micrograph and molecular formula of amorphous Micetinib nanoparticles, scale-100 nm.
FIG. 22 is a transmission electron micrograph and molecular formula of amorphous gefitinib nanoparticles, scale-100 nm.
FIG. 23 is a transmission electron micrograph and molecular formula of amorphous imatinib nanoparticles, scale-100 nm.
FIG. 24 is a transmission electron micrograph and molecular formula of amorphous camptothecin nanoparticles, scale-100 nm.
FIG. 25 is a transmission electron micrograph and molecular formula of amorphous griseofulvin nanoparticles, scale-100 nm.
FIG. 26 is a transmission electron micrograph and molecular formula of amorphous celecoxib nanoparticles, scale-100 nm.
FIG. 27 is a transmission electron micrograph and molecular formula of amorphous sirolimus nanoparticles, scale-100 nm.
FIG. 28 is a transmission electron micrograph and molecular formula of amorphous aprepitant nanoparticles, scale-100 nm.
FIG. 29 is a transmission electron micrograph of amorphous fenofibrate nanoparticles and molecular formula, scale-100 nm.
FIG. 30 is a transmission electron micrograph and molecular formula of amorphous nepafenac nanoparticles, scale-100 nm.
FIG. 31 is a transmission electron micrograph and molecular formula of amorphous sodium dantrolene nanoparticles, scale-100 nm.
FIG. 32 is a transmission electron micrograph and molecular formula of amorphous paliperidone palmitate nanoparticles, scale-100 nm.
FIG. 33 is a transmission electron micrograph and molecular formula of amorphous 10-hydroxycamptothecin nanoparticles, scale-100 nm.
FIG. 34 is a transmission electron micrograph and molecular formula of amorphous megestrol nanoparticles, scale-100 nm.
Detailed Description
The drug or drug intermediate in the present invention means that a single crystal or amorphous substance exists. The medicament is a medicament used by any organism, including but not limited to the human body, animal and plant bodies, etc., in order to maintain the normal operation of the organism.
The drug intermediate is used for preparing the drug, and single crystal or amorphous substances exist.
In the present invention, "optionally" means with or without subsequent steps.
In the invention, the amorphous substance of the drug or the drug intermediate is the amorphous drug or the drug intermediate.
[ method for producing Single Crystal or amorphous Material ]
As previously described, the present invention provides a method of preparing a single crystal or amorphous form of a drug or drug intermediate, the method comprising the steps of:
(a1) Preparing a solution of a drug or drug intermediate, wherein the solvent from which the solution is prepared is a freezable solvent;
(a2) Freezing, optionally curing, the solution of the drug or drug intermediate of step (a 1) to produce a frozen solvent mixture comprising single crystals or amorphous forms of the drug or drug intermediate; optionally, the composition may be used in combination with,
(a3) Separating the single crystal or amorphous form of the drug or drug intermediate from the mixed system of step (a 2).
[ method for producing Single Crystal ]
As described above, the present invention provides a method for producing a single crystal of a drug or a drug intermediate, the method comprising the steps of:
(a1) Preparing a solution of a drug or drug intermediate, wherein the solvent from which the solution is prepared is a freezable solvent;
(a2) Freezing, optionally curing, the solution of the drug or drug intermediate of step (a 1) to produce a mixed system of frozen solvent containing single crystals of the drug or drug intermediate; optionally, the composition may be used in combination with,
(a3) Separating the single crystal of the drug or drug intermediate from the mixed system of step (a 2);
wherein the heating or cooling rate in the curing process is less than 10 ℃/min, and/or the curing time in the curing process is at least 25min.
Illustratively, in the curing process, the temperature is raised or lowered to a certain temperature at a speed of less than 10 ℃/min, and the mixture is maintained for a period of time, so as to obtain a mixed system of frozen solvent of single crystals containing the drug or the drug intermediate.
Illustratively, in the curing process, the temperature is raised or lowered at any rate to a certain temperature, and the mixture is cured for at least 25min to obtain a mixed system of frozen solvent of single crystal containing the drug or drug intermediate.
Illustratively, in the curing process, the temperature is raised or lowered to a certain temperature at a speed of less than 10 ℃/min, and the mixture is cured for at least 25min, so as to obtain a mixed system of the frozen solvent of the single crystal containing the drug or the drug intermediate.
Illustratively, the certain temperature reached is, for example, equal to or less than 0 ℃, and also, for example, equal to or less than-5 ℃; in particular, it may be-10 ℃, -15 ℃, -18 ℃, -20 ℃, -24 ℃, -25 ℃, -30 ℃, -72 ℃, -80 ℃, -90 ℃, -100 ℃ or liquid nitrogen temperature, etc.
As mentioned above, the heating or cooling rate is less than 10℃per minute, for example, less than 9℃per minute, and further for example, less than or equal to 5℃per minute. It will be understood that if the rate is 0℃per minute, curing is performed while maintaining the same temperature as the freezing temperature.
As described above, the aging time is at least 25min, and may be, for example, 30min, 40min, 50min, 55min, 60min, 90min, 100min, 120min, 150min, 200min, 300min, 500min or more, etc.
Illustratively, the drug or drug intermediate is selected from at least one of the following:
chloramphenicol, penicillin G sodium salt, baicalein, carbenicillin disodium salt, nafcillin sodium monohydrate, and ginsenoside Rh 2 Ginsenoside Rd and ginsenoside Rb 2 Alternaria schneideriana (schneid.) schneidElement A 1 Gibberellin A 5 Baicalin, scutellarin, beta-sitosterol, brassicasterol, jasmonic acid and p-toluenesulfonic acid.
[ method for producing amorphous substance ]
As previously described, the present invention provides a method of preparing an amorphous drug or drug intermediate, the method comprising the steps of:
(a1) Preparing a solution of a drug or drug intermediate, wherein the solvent from which the solution is prepared is a freezable solvent;
(a2) Freezing and curing the solution of the drug or the drug intermediate in the step (a 1) to prepare a mixed system containing the amorphous frozen solvent of the drug or the drug intermediate; optionally, the composition may be used in combination with,
(a3) Separating the amorphous form of the drug or drug intermediate from the mixed system of step (a 2);
wherein the heating or cooling rate in the curing process is more than or equal to 10 ℃/min, and the curing time in the curing process is less than 25min.
Illustratively, in the curing process of the step (a 2), the temperature is cured for less than 25 minutes at a temperature rising or reducing speed of more than or equal to 10 ℃/min, so as to obtain the mixed system of the frozen solvent of the amorphous substance containing the drug or the drug intermediate.
In one embodiment, the greater the difference between the certain temperature reached and the freezing temperature, the greater the particle size of the resulting amorphous material. The particle size of the obtained amorphous material can be controlled by adjusting the temperature. Illustratively, the certain temperature reached is, for example, equal to or less than 0 ℃, and also, for example, equal to or less than-5 ℃; in particular, -5 ℃, -7 ℃, -8 ℃, -10 ℃, -12 ℃, -20 ℃, -45 ℃, etc. Preferably, the temperature is raised from the liquid nitrogen temperature to the above temperature at a temperature rise rate of 10 ℃/min or more.
As described above, the heating or cooling rate is 10 ℃/min or more, for example 15 ℃/min, 16 ℃/min, 17 ℃/min, 18 ℃/min, 19 ℃/min, 20 ℃/min, 21 ℃/min, 22 ℃/min, 23 ℃/min, 24 ℃/min, 25 ℃/min, 26 ℃/min, 27 ℃/min, 28 ℃/min, 29 ℃/min, 30 ℃/min or more; the aging time is less than 25 minutes, and may be, for example, 25 minutes, 23 minutes, 22 minutes, 21 minutes, 20 minutes, 19 minutes, 18 minutes, 17 minutes, or 16 minutes.
Illustratively, the drug or drug intermediate is selected from at least one of the following:
paclitaxel, meratinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib, sirolimus, aprepitant, fenofibrate, nepafenac, dantrolene sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol.
[ embodiment of the above method ]
According to an embodiment of the present invention, in step (a 1), the preparation of the solution of the drug or drug intermediate is carried out using procedures known to those skilled in the art, such as standard solution preparation methods.
According to an embodiment of the present invention, in step (a 1), the freezable solvent includes, but is not limited to, water and/or an organic solvent.
The water includes, but is not limited to, secondary water, distilled water, ultrapure water.
The organic solvent capable of freezing refers to an organic solvent capable of forming a solid state at a certain temperature and a certain pressure.
The freezable 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, acid and anhydride organic solvents, ester organic solvents, nitrogen-containing compound organic solvents, sulfur-containing compound organic solvents, multifunctional group organic solvents, and the like.
The hydrocarbon organic solvent includes 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, and the like; the halogenated hydrocarbon organic solvent is a halogen-substituted hydrocarbon organic solvent as described above, such as methylene chloride, chloroform, carbon tetrachloride, ethyl chloride, ethylene dichloride, trichloroethane, dibromomethane, bromoethane, dibromoethane, dibromopropane, chlorobenzene, dichlorobenzene, dichlorotoluene, dibromobenzene, etc., and the alcohol solvent includes, for example: methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, 2-methyl-1-butanol, cyclic ethanol, phenethyl alcohol, ethylene glycol, propylene glycol, glycerol, butylene glycol, pentylene glycol, ethylene glycol, and the like; the phenolic solvents are, for example: phenol, benzenediol, cresol, xylenol, and the like; the ether and acetal solvents are, for example: methyl ether, ethyl 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, diglyme, glycerol ether, crown ether, benzaldehyde, cinnamaldehyde, and the like; the ketone solvents are, for example: acetone, methyl ethyl ketone, methyl acetone, pentanone, cyclohexanone, acetophenone, and the like; 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 cinnamate, dimethyl phthalate, butyrolactone, and the like; the nitrogen-containing compound solvent includes nitro solvents, nitrile solvents, amine solvents, amide solvents, lactam solvents, and the like, and examples thereof are: nitroethane, nitrobenzene, acetonitrile, propionitrile, methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, aniline, pyrrole, tetrahydropyrrole, piperidine, pyridine, tetrahydropyridine, ethylenediamine, propylenediamine, formamide, acetamide, N-dimethylformamide, N-dimethylacetamide, pyrrolidone, N-methylpyrrolidone, caprolactam, and the like; the sulfur-containing compounds are, for example: carbon disulfide, methyl sulfide, thiophene, tetrahydrothiophene, dimethyl sulfoxide, dimethyl sulfone, and the like; the polyfunctional solvent is, for example: ethylene glycol monomethyl ether, diethylene glycol, polyethylene glycol, polypropylene glycol, 2-chloroethanol, allyl alcohol, acrylonitrile, diethanolamine, p-methoxybenzyl alcohol, morpholine, N-methylmorpholine, lactic acid, methyl acetoacetate, ethyl acetoacetate, and the like.
According to an embodiment of the present invention, the organic solvent further includes a combination of the above-mentioned plurality of organic solvents.
In the present invention, the drug includes natural drugs (such as plant drugs, antibiotics, biochemical drugs, etc.), synthetic drugs or genetically engineered drugs.
Further, the medicaments include medicaments for the human body including, but not limited to: antibiotic drugs, cardiovascular and cerebrovascular drugs, digestive system drugs, respiratory system drugs, urinary system drugs, blood system drugs, five sense organs drugs, antirheumatic drugs, diabetes drugs, hormonal drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins, etc.
The medicaments also include medicaments for animals and plants, including but not limited to: antimicrobial agents, antiparasitic agents, antiseptic agents, agents acting on the central nervous system, agents acting on the autonomic nervous system, narcotics and their auxiliary agents, corticosteroids, digestive system agents, respiratory system agents, urinary system agents, circulatory system agents, reproductive system agents, blood and hematopoietic system disease agents, vitamins and minerals, agents regulating water, electrolytes, acid-base balance, antidotes and antiallergic agents, topical agents and pharmaceutical excipients, probiotics, plant growth regulators, pesticides, bactericides, and the like.
The drug intermediate refers to a compound capable of preparing the drug. Including antibiotic-type medicine preparation, cardiovascular-cerebrovascular-type medicine preparation, digestive-type medicine preparation, respiratory-type medicine preparation, urinary-type medicine preparation, blood-type medicine preparation, five-sense organ-type medicine preparation, antirheumatic-type medicine preparation, diabetes-type medicine preparation, hormone-type medicine preparation, dermatological-type medicine preparation, gynecological-type medicine preparation, antitumor-type medicine preparation, antipsychotic-type medicine preparation, nervous-type medicine preparation, vitamin-type medicine preparation, etc.
According to an embodiment of the present invention, the drug or drug intermediate may be a hydrophilic drug or a hydrophobic drug.
Illustratively, the drug or drug intermediate is selected from at least one of the following: paclitaxel, meratinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib, sirolimus, aprepitant, fenofibrate, nepafenac, dantrolene sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol, chloramphenicol, penicillin G sodium salt, baicalein, carbenicillin disodium salt, nafcillin sodium monohydrate, ginsenoside Rh 2 Ginsenoside Rd and ginsenoside Rb 2 Gibberellin A 1 Gibberellin A 5 Baicalin, scutellarin, beta-sitosterol, brassicasterol, jasmonic acid and p-toluenesulfonic acid.
According to an embodiment of the invention, the drug or drug intermediate has a certain solubility in the solvent; it will be appreciated by those skilled in the art that the amount of the drug or drug intermediate dissolved in the solvent may be any, i.e., the drug or drug intermediate may be dissolved in the solvent, and the amount thereof dissolved in the solvent is not particularly limited; it will be appreciated that the solubility of the drug or drug intermediate in the solvent may be poorly soluble, slightly soluble, soluble and readily soluble.
According to an embodiment of the present invention, preferably, the drug or the drug intermediate is dissolved in the solvent in an amount of 1×10 or more -7 g/100g (solvent used), for example, 0.001g/100g (solvent used) or more, such as 0.01g/100g (solvent used) or more, such as 0.1g/100g (solvent used) or more, such as 1g/100g (solvent used) or more, such as 10g/100g (solvent used) or more.
According to an 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 will be appreciated by those skilled in the art, the drug or drug intermediate may be in a solvent which is either an unsaturated or saturated solution or which is supersaturated; of course, the concentration of the solution of the drug or the drug intermediate has great influence on the aggregation rate of the drug or the drug intermediate, and when the concentration is low, the aggregation rate of the drug or the drug intermediate is low, and the time required for obtaining the monocrystal or the amorphous substance is correspondingly increased; at higher concentrations, the drug or drug intermediate aggregates faster and the time required to obtain single crystals or amorphous material is correspondingly reduced. Therefore, the preparation time of single crystals or amorphous matters is regulated and controlled through the solution concentration by reasonably selecting the concentration; of course, the time for preparing the single crystal or amorphous form is not only dependent on the concentration of the solution, but is also closely related to maturation.
According to an embodiment of the present invention, the concentration of the solution of the drug or drug intermediate is 1×10 or more - 7 g/100g (solvent used), for example, 0.001g/100g (solvent used) or more, such as 0.01g/100g (solvent used) or more, such as 0.1g/100g (solvent used) or more, such as 1g/100g (solvent used) or more, such as 10g/100g (solvent used) or more. The upper limit of the concentration of the organic solvent solution of the drug or drug intermediate is not particularly limited, and may be a supersaturated solution or a saturated solution of the drug or drug intermediate in a solvent.
Preferably, the concentration of the solution of the drug or drug intermediate is 1X 10 -7 g/100g (solvent used) to 1g/100g (solvent used).
According to the invention, said step (a 2) comprises in particular the steps of:
cooling and freezing the solution of the medicine or the medicine intermediate in the step (a 1) into solid, and optionally curing to prepare the obtained mixed system.
In the present invention, the inventors have unexpectedly found that the solution freezes to a solid during freezing, whereas the drug or drug intermediate dissolved in the solution achieves concentration aggregation at the solvent interface, providing the possibility of forming single crystals or amorphous forms. In addition, the frozen solution of the drug or drug intermediate, when subjected to the freezing process and optionally further aging process, becomes gradually larger in the grain size formed by the solvent, so that the drug or drug intermediate is continuously aggregated at the interface of each crystal, is continuously grown and forms an amorphous substance or single crystal, and finally, drug nanoparticles having a particle size of several tens nm to several hundreds nm can be obtained as shown in fig. 17. Taking the example of a water system, to demonstrate that ice crystals accumulate at their interface during freezing, or optionally further maturation, the aggregation luminescent material AIE35 was chosen to verify the process (aggregation luminescent material in the free molecular state, any wavelength does not excite it to emit light, but the molecule is excited to fluoresce when present in the aggregated state). During the experiment, the aqueous AIE35 solution was frozen to a solid by either means, and the ice formed a separate polycrystalline system, as shown in fig. 18, at the interface between any two contacting ice crystals, AIE35 formed aggregates and crystallized. As can be seen from FIG. 18A, fluorescence at the interface is enhanced, indicating that AIE35 molecules can aggregate at the interface and gradually overform AIE35 nano-single crystals from amorphous material. And as can be seen from B in fig. 18, the aggregates formed at the interface undergo a transition from an amorphous state to a single crystal, and the volume of the single crystal thereof gradually increases. Wherein fig. 18 shows transmission electron microscopy and electron diffraction characterization results.
The molecular structure of AIE35 is:
in order to further prove the principle of monocrystal formation, the method adopts p-toluenesulfonic acid molecules, adopts a transmission electron microscope to attenuate total reflection infrared at a low temperature in situ, and observes the aggregation of the p-toluenesulfonic acid in the freezing and curing processes of water and forms the monocrystal and the continuous growth process of the monocrystal. The detection result shows that the freezing process forms a p-toluenesulfonic acid monocrystal which grows gradually when being cured, and the characteristic peak of the p-toluenesulfonic acid is 1035cm -1 The generation and blue shift of (the stretching vibration of sulfonate) also strongly demonstrates that as curing proceeds, the p-toluenesulfonic acid molecules accumulate continuously so that the single crystal formed grows continuously (see fig. 19).
According to an embodiment of the present invention, the freezing includes, but is not limited to, complete freezing, incomplete freezing. As will be appreciated by those skilled in the art, by completely frozen is meant that the solution of the drug or drug intermediate is completely frozen as a solid; the incomplete freezing means that the solution of the drug or drug intermediate is partially frozen into a solid and partially is also in a liquid state.
According to embodiments of the present invention, it will be appreciated by those skilled in the art that the freezing may be by any one or more cooling methods to freeze a solution of a drug or drug intermediate having any volume and shape into a solid or solid-liquid mixture in any one or more cooling processes. I.e. the freezing is the freezing of a solution of the drug or drug intermediate into a solid or solid-liquid mixture. Compared with the traditional evaporation method and cooling crystallization method, the freezing crystallization method has a larger regulating and controlling range for the concentration of the solution of the medicine or the medicine intermediate, and the time for obtaining the medicine or the medicine intermediate monocrystal is greatly shortened.
According to the embodiment of the present invention, the freezing time, freezing temperature gradient, freezing method, freezing process, etc. are not particularly limited, and any volume and shape of the solution of the drug or drug intermediate may be frozen as a solid or a solid-liquid mixture. Of course, the concentration of the solution of the drug or drug intermediate may also be selected reasonably during the freezing process in order to control the diffusion rate of the drug or drug intermediate and thereby affect the crystallization process. For example, if the concentration of the drug or drug intermediate solution is high, the freezing time selected at this time may be suitably shortened and the freezing temperature may be suitably lowered; the purpose of this is to prevent the drug or drug intermediate in the higher concentration solution from forming polycrystals with difficulty in control; if the concentration of the drug or drug intermediate solution is low, the freezing time selected at this time can be prolonged appropriately, and the freezing temperature can be increased appropriately; the purpose of such an operation is to achieve efficient aggregation of the drug or drug intermediate and, in turn, controlled formation of an amorphous or single crystal.
According to the embodiment of the invention, the freezing method is an operation mode known to a person skilled in the art, such as cooling and freezing operation by using any refrigeration device or cooling and freezing by using any low-temperature substance; illustratively, the freezing method includes, but is not limited to, one or more of compression refrigeration equipment de-chilling, semiconductor refrigeration equipment de-chilling, liquid nitrogen de-chilling, liquid helium de-chilling, liquid carbon dioxide de-chilling, liquid oxygen de-chilling, liquid ethane de-chilling, dry ice de-chilling, etc.
The operation pressure of the freezing is not limited as well, and may be freezing under normal pressure or freezing treatment under high pressure or low pressure.
According to embodiments of the present invention, the freezing process is a manner of operation known to those skilled in the art, such as by any process that freezes a solution of a drug or drug intermediate from a liquid state to a solid state, illustratively including, but not limited to, one or a combination of freezing processes of rapid cooling, slow cooling, stepwise cooling, first warming and then cooling, and the like.
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 formed by freezing the solution of the drug or drug intermediate are not particularly limited as long as the solid or solid-liquid mixture can be obtained by freezing the solid; it will be appreciated by those skilled in the art that the freezing may be by freezing any volume of the solution of the drug or drug intermediate as a whole, or by freezing any volume of the film formed from the solution of the drug or drug intermediate, or by freezing any volume of the droplets formed from the solution of the drug or drug intermediate.
According to an embodiment of the invention, the dissolution of a drug or drug intermediate frozen into a solid or solid-liquid mixtureThe liquid may optionally be further subjected to a maturation treatment; the curing temperature, curing time and curing process in the curing process are not particularly limited, but the frozen medicine or medicine intermediate solution in the curing process is required to be ensured to be at least partially or completely kept in a solid state, namely the frozen medicine or medicine intermediate solution in the curing process is required to be kept in a frozen state; curing the solid, for example, by the same method as the freezing treatment, or by another method; the curing treatment aims to realize the regulation and control of aggregation of the medicine or the medicine intermediate and the growth speed of the nano-particles, so as to obtain single crystals or amorphous substances of the medicine or the medicine intermediate. As will be appreciated by those skilled in the art, the maturation temperature should be below a temperature at which the frozen drug or drug intermediate solution will re-melt (i.e., T Melting ) Preferably, the curing temperature is lower than T Melting At 5 ℃ or higher, more preferably lower than T Melting At a temperature of 10 ℃ or above.
According to an embodiment of the present invention, the maturation process is the residence of a solution of the drug or drug intermediate in a frozen state for a period of time. The frozen state may be either completely frozen or not completely frozen, and may be selected according to operations known to those skilled in the art.
According to the embodiment of the invention, the curing process adopts a rapid heating (or cooling) or slow heating (or cooling) mode, for example, the heating or cooling rate of the curing process is greater than or equal to 10 ℃/min, and the heating or cooling rate in the range can enable the medicine or the medicine intermediate to be quickly released from the solid mixture and generate disordered aggregation, so that the preparation of the amorphous substance is ensured by limiting the curing time.
Illustratively, the rate of temperature rise or decrease during the ripening is less than 10 ℃/min, which range of temperature rise or decrease results in slow release of the drug or drug intermediate from the solid mixture and thus in ordered aggregation, allowing the preparation of single crystals.
According to the embodiment of the invention, the curing temperature (i.e. the temperature reached) controls the size of crystal grains of the frozen solvent and further controls the aggregation speed of the medicine or the medicine intermediate, namely, the larger the temperature difference between the curing temperature and the freezing temperature is, the larger the crystal grain size of the frozen solvent is, the faster the aggregation speed of the medicine or the medicine intermediate is, and the shorter the time required for forming single crystals or amorphous matters is, so that the particle size of the single crystals or the amorphous matters of the prepared medicine or medicine intermediate is also larger; the smaller the difference between the curing temperature and the freezing temperature, the smaller the grain size of the freezing solvent, the slower the aggregation speed of the medicine or the medicine intermediate, the longer the time required for forming the monocrystal or the amorphous substance, and the smaller the grain size of the monocrystal or the amorphous substance of the prepared medicine or medicine intermediate. That is, the larger the difference between the aging temperature and the freezing temperature, the larger the particle size of the single crystal or amorphous substance of the prepared drug or drug intermediate.
The curing time is not particularly limited according to the embodiment of the present invention, and may be a process known to those skilled in the art, and as can be seen from the above description of the mechanism of the method of the present application, the curing process may be understood as nucleation and growth of an amorphous substance or formation and growth of a single crystal, and a proper extension of the curing time may be achieved, so that an amorphous or single crystal having a complete particle size and morphology may be obtained, but it should be noted that since the nature of adjusting the curing time regulates the concentration of aggregation of a drug or a drug intermediate, too long curing may cause the concentration of aggregation to be too high, which may be disadvantageous to form an amorphous substance or a single crystal. Illustratively, the time of maturation is greater than 1 picosecond, preferably the time of maturation is from 1 to 1000 minutes, and more preferably the time of maturation is from 10 to 300 minutes.
Illustratively, the curing time is less than 25 minutes, and the preparation of the amorphous material can be achieved by regulating the rate of temperature rise or temperature reduction with the curing process. When the curing time is at least 25min, the aggregation concentration of the drug or the drug intermediate can be further regulated, for example, a single crystal can be prepared. However, the aging time must not be too long, and the aging time may be too long to further change the known single crystal into a polycrystalline structure.
According to the embodiment of the invention, any refrigerating device or any low temperature can be adopted in the curing process, so that the solution of the medicine or the medicine intermediate is kept in a frozen state; for example, natural cooling, compression refrigeration, semiconductor refrigeration, or a combination of one or more of liquid nitrogen, liquid helium, liquid carbon dioxide, liquid oxygen, liquid ethane, dry ice, etc.
According to an embodiment of the invention, in step (a 3), the separation may be physical and/or chemical separation of the solvent frozen to a solid from the system. After freezing or optionally further ripening, single crystals or amorphous materials have been prepared which are present at the solvent crystal interface and need to be separated by suitable means; or the solvent is removed.
According to embodiments of the present invention, the physical means include, but are not limited to, one or a combination of quench separation, sublimation (e.g., vacuum sublimation), dissolution. The sublimation can be performed, for example, by freeze-drying; the vacuum sublimation can be performed, for example, by freeze-drying under vacuum; the dissolution is, for example, a dissolution of the frozen solvent with another liquid solvent.
According to embodiments of the present invention, the chemical means includes, but is not limited to, one or a combination of chemical reactions, electrolysis.
According to the invention, the method further comprises the steps of:
(a4) Collecting the single crystal or amorphous substance obtained in the step (a 3).
According to an embodiment of the present invention, in step (a 4), the collecting includes, but is not limited to, collecting with one or a combination of several of optical microscopy, scanning electron microscopy, dual beam electron microscopy, transmission electron microscopy.
[ method of growing Single Crystal ]
As described above, the present invention also provides a method of growing a single crystal, the method including the above method of producing a single crystal.
According to an embodiment of the present invention, the method of growing a single crystal further comprises the steps of:
(b1) Transferring the prepared single crystal of the medicine or the medicine intermediate into a mother solution of the medicine or the medicine intermediate for culture;
(b2) Collecting the single crystal of step (b 1).
According to embodiments of the present invention, the transfer is any method known to those skilled in the art capable of transferring single crystals, including, but not limited to, one or a combination of several of optical microscope transfer, scanning electron microscope transfer, dual beam electron microscope transfer, transmission electron microscope transfer.
According to an embodiment of the invention, the mother liquor is a mother liquor system which is known to the person skilled in the art and is adapted to the single crystal to be cultivated, for example, a saturated solution system, a supersaturated solution system or an unsaturated solution system; for example when the substance to be crystallised is chloramphenicol; an aqueous solution of chloramphenicol was used as the mother liquor.
The preparation method of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the examples described below are commercially available unless otherwise specified.
The aging time described in the following examples means the time required for heating to the aging temperature after the freezing process is completed, and the time for maintaining at the aging temperature; the maintaining time refers to the time maintained at the curing temperature.
Example 1
Preparing a chloramphenicol solution with the concentration of 1mM by using water, taking 1mL of the solution by using a syringe, spreading the solution on a silicon wafer, slowly cooling to be completely frozen in a refrigerator with the temperature of-24 ℃, finally curing the solution in the refrigerator with the temperature of-10 ℃ for 20min (the temperature rising rate is less than 10 ℃/min), and then freeze-drying the sample to completely sublimate solid water (ice), thereby obtaining the chloramphenicol single crystal. And finally, selecting a single crystal with better quality from the beaker (the selection method is a routine choice of a person skilled in the art, for example, is judged by a morphology structure), moving the single crystal to a saturated chloramphenicol water solution, and placing the solution in a constant temperature and humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the chloramphenicol single crystal with larger volume, wherein the drawing is shown in fig. 1.
Example 2
Preparing chloramphenicol solution with concentration of 10mM with water, taking 100ml of solution into beaker, slowly cooling to complete freezing in-24deg.C refrigerator, aging in-10deg.C refrigerator for 30min, quenching, and rapidly removing frozen ice to obtain monocrystal. And finally, selecting a monocrystal with better quality from the silicon chip, transferring the monocrystal to a saturated chloramphenicol aqueous solution, and placing the saturated chloramphenicol aqueous solution in a constant temperature and constant humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the chloramphenicol monocrystal with larger volume.
Example 3
A chloramphenicol solution with the concentration of 20mM is prepared by water, 20 mu L of the solution is taken by a pipette, the solution is dripped to a silicon wafer with the temperature of-90 ℃, the temperature of the silicon wafer is controlled by a cold and hot table, and then the temperature is raised to-8 ℃ at the heating rate of 8 ℃/min, and the temperature is maintained for 20min. And then quenching to remove frozen ice to obtain chloramphenicol monocrystal, selecting a monocrystal with better quality from the silicon chip, transferring the monocrystal to a saturated chloramphenicol aqueous solution, and placing the saturated chloramphenicol aqueous solution in a constant temperature and constant humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the chloramphenicol monocrystal with larger volume.
Example 4
Preparing penicillin G sodium salt solution with concentration of 1mM by water, taking 100ml of the solution into a beaker by using a dosage cylinder, slowly cooling to be completely frozen in a refrigerator with the temperature of-24 ℃, finally curing for 90min in a refrigerator with the temperature of-20 ℃, and then freeze-drying the sample to completely sublimate ice to obtain the monocrystal. And finally, selecting a better-quality single crystal from a beaker, transferring the single crystal to a saturated penicillin G sodium salt aqueous solution, and placing the solution in a constant temperature and constant humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the penicillin G sodium salt single crystal with larger volume, wherein the penicillin G sodium salt aqueous solution is shown in a figure 2.
Example 5
Preparing penicillin G sodium salt solution with the concentration of 100 mu M by using water, taking 15 mu L of the solution by using a liquid-transferring gun, dripping the solution to a silicon wafer with the temperature of-90 ℃, controlling the temperature of the silicon wafer by a cold-hot table, then raising the temperature to-10 ℃ at the heating rate of 10 ℃/min, and maintaining the temperature for 30min. And freeze-drying the sample to sublimate the solid ice completely, then selecting a single crystal with better quality from the silicon wafer, transferring the single crystal to a saturated penicillin G sodium salt solution, and placing the solution in a constant temperature and humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the penicillin G sodium salt single crystal with larger volume.
Example 6
Preparing baicalein solution with concentration of 1mM with dimethyl sulfoxide, taking 15 μl of the solution with a pipette, dripping onto silicon wafer at-90deg.C, controlling the temperature of the silicon wafer by a cold and hot stage, heating to-18deg.C at a heating rate of 10deg.C/min, and maintaining at that temperature for 40min. And freeze-drying the sample to sublimate the solid dimethyl sulfoxide completely, then selecting a single crystal with better quality from the silicon wafer, transferring the single crystal to a saturated baicalein solution, and placing the solution in a constant temperature and constant humidity environment with the temperature of 25 ℃ and the relative humidity of 40% for a period of time to grow the baicalein single crystal with larger volume, as shown in figure 10.
Examples 7 to 35
The procedure is as in example 1, with the following differences:
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the embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (30)
1. A method for producing a single crystal of a drug or a drug intermediate, which is different from a conventional evaporation method and a cooling crystallization method, by using solution freezing to induce crystallization of the drug or drug intermediate,
The method for preparing the single crystal of the drug or the drug intermediate comprises the following steps:
(a1) Preparing a solution of a drug or drug intermediate, the solution of the drug or drug intermediate consisting of the drug or drug intermediate and a freezable solvent;
(a2) Freezing and curing the solution of the drug or the drug intermediate in the step (a 1) to prepare a mixed system of frozen solvent of single crystal containing the drug or the drug intermediate;
wherein the heating or cooling rate in the curing process is less than 10 ℃/min, and/or the curing time in the curing process is at least 25min; the drug or drug intermediate is dissolved in the solution before concentration aggregation is achieved at the interface of the solvent in the solid state;
optionally, (a 3) isolating a single crystal of the drug or drug intermediate from the mixed system of step (a 2);
the freezing is to convert the solution of the drug or the drug intermediate in the step (a 1) from a liquid state to a solid state, the curing process is to keep the solution of the drug or the drug intermediate in a frozen state for a period of time, the solvent is frozen to be a solid in the freezing process, concentration aggregation of the drug or the drug intermediate dissolved in the solution is realized at the interface of the solvent in the solid state, namely, the drug or the drug intermediate is released and aggregated at the interface of the solvent in the solid state while the solvent is frozen to be the solid state in the freezing process, and the release and aggregation rate of the drug or the drug intermediate in the solvent is further regulated and controlled through regulating and controlling the crystallization process of the solvent and the recrystallization process of the crystallized solvent, so that the single crystal of the drug or the drug intermediate is formed.
2. The method according to claim 1, wherein the temperature is allowed to reach a certain temperature at a heating or cooling rate of less than 10 ℃/min during the aging process, and the aging is performed for at least 25min, thereby obtaining a mixed system of frozen solvent of single crystals containing the drug or drug intermediate.
3. The method of claim 1, wherein the drug comprises a natural drug, a synthetic drug, or a genetically engineered drug.
4. The method of claim 1, wherein the medication comprises at least one of the following medications for the human body: antibiotic drugs, cardiovascular and cerebrovascular drugs, digestive system drugs, respiratory system drugs, urinary system drugs, blood system drugs, five sense organs drugs, antirheumatic drugs, diabetes drugs, hormone drugs, dermatological drugs, gynecological drugs, antitumor drugs, antipsychotic drugs, nervous system drugs, vitamins.
5. The method of claim 1, wherein the medicament further comprises at least one of the following medicaments for animals and plants: antimicrobial agents, antiparasitic agents, antiseptic agents, agents acting on the central nervous system, agents acting on the autonomic nervous system, narcotics and their auxiliary agents, corticosteroids, agents of the digestive system, agents of the respiratory system, agents of the urinary system, agents of the circulatory system, agents of the reproductive system, agents of the blood and hematopoietic system, vitamins and minerals, agents regulating water, electrolytes, acid-base balance, antidotes and antiallergic agents, topical agents and pharmaceutical excipients, probiotics, plant growth regulators, pesticides, bactericides.
6. The method according to any one of claims 3 to 5, wherein the pharmaceutical intermediate is a compound for preparing the drug, including a compound for preparing an antibiotic drug, a compound for preparing a cardiovascular and cerebrovascular drug, a compound for preparing a digestive system drug, a compound for preparing a respiratory system drug, a compound for preparing a urinary system drug, a compound for preparing a blood system drug, a compound for preparing a five sense organ drug, a compound for preparing an antirheumatic drug, a compound for preparing a diabetes, a compound for preparing a hormone drug, a compound for preparing a dermatological drug, a compound for preparing a gynecological drug, a compound for preparing an antitumor drug, a compound for preparing an antipsychotic drug, a compound for preparing a nervous system drug, a compound for preparing a vitamin.
7. The method of claim 1 or 2, wherein the drug or drug intermediate is a hydrophilic drug or a hydrophobic drug.
8. The method according to claim 1 or 2, wherein the drug or drug intermediate is selected from at least one of the following: paclitaxel, meratinib, gefitinib, imatinib, camptothecin, griseofulvin, celecoxib, sirolimus, aprepitant, fenofibrate, nepafenac, dantrolene sodium, paliperidone palmitate, 10-hydroxycamptothecin, megestrol, chloramphenicol, penicillin G sodium salt, baicalein, carbenicillin disodium salt, nafcillin sodium monohydrate, ginsenoside Rh 2 Ginsenoside Rd and ginsenoside Rb 2 Gibberellin A 1 Gibberellin A 5 Baicalin, scutellarin, beta-sitosterol, brassicasterol, jasmonic acid and p-toluenesulfonic acid.
9. The method according to claim 1 or 2, wherein in step (a 1) the freezable solvent comprises water and/or an organic solvent.
10. The method according to claim 1 or 2, wherein in step (a 1) the drug or drug intermediate is soluble, slightly soluble or poorly soluble in a solvent.
11. The method according to claim 1 or 2, wherein the amount of the drug or the drug intermediate dissolved in the solvent is 1 x 10 or more -7 g/100g of solvent used.
12. The method according to claim 11, wherein the amount of the drug or drug intermediate dissolved in the solvent is 0.001g/100g or more of the solvent used.
13. The method according to claim 12, wherein the amount of the drug or drug intermediate dissolved in the solvent is 0.01g/100g or more of the solvent used.
14. The method according to claim 13, wherein the amount of the drug or drug intermediate dissolved in the solvent is 0.1g/100g or more of the solvent used.
15. The method according to claim 14, wherein the drug or drug intermediate is dissolved in the solvent in an amount of 1g/100g or more of the solvent used.
16. The method according to claim 15, wherein the drug or drug intermediate is dissolved in the solvent in an amount of 10g/100g or more of the solvent used.
17. The method according to claim 1 or 2, wherein the step (a 2) comprises in particular the steps of:
cooling and freezing the solution of the drug or the drug intermediate in the step (a 1) into a solid mixture, and optionally curing to prepare a mixed system of frozen solvent of single crystal containing the drug or the drug intermediate.
18. The method according to claim 1 or 2, wherein the freezing method comprises one or a combination of several of 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 freezing, dry ice cooling freezing, ice cooling freezing.
19. The method of claim 1 or 2, wherein the freezing process comprises one or a combination of freezing processes of rapid cooling, slow cooling, stepwise cooling, first warming and then cooling.
20. The method of claim 1 or 2, wherein the freezing comprises complete freezing or incomplete freezing.
21. A method according to claim 1 or 2, wherein in step (a 3) the separation is by physically and/or chemically separating the solvent frozen to a solid from the mixed system.
22. The method of claim 21, wherein the physical means comprises one or a combination of quench separation, sublimation, dissolution;
the chemical mode comprises one or a combination of a plurality of modes of chemical reaction and electrolysis.
23. The method according to claim 1 or 2, characterized in that the method further comprises the steps of:
(a4) Collecting the single crystal prepared in the step (a 3).
24. The method of claim 23, wherein in step (a 4), the collecting comprises employing one or a combination of several of optical microscopy, scanning electron microscopy, dual beam electron microscopy, transmission electron microscopy.
25. A method of growing a single crystal of a drug or drug intermediate, comprising the method of preparing a single crystal of a drug or drug intermediate according to any one of claims 1 to 24.
26. The method of claim 25, wherein the method of growing a single crystal of a drug or drug intermediate further comprises the steps of:
(b1) Transferring the prepared single crystal of the medicine or the medicine intermediate into a mother solution of the medicine or the medicine intermediate for culture;
(b2) Collecting the single crystal of step (b 1).
27. The method according to claim 26, wherein in the step (b 1), the transferring is to transfer the mixed system of the single crystal containing the drug or the drug intermediate and the frozen solvent of the step (a 2) into a mother liquor of the drug or the drug intermediate for single crystal cultivation; or transferring the single crystal after the solvent is removed in the step (a 3) into a mother solution of a drug or a drug intermediate directly for single crystal culture; or transferring the single crystal collected in the step (a 4) into a mother solution of a drug or drug intermediate for single crystal cultivation.
28. The method of claim 26, wherein said transferring comprises one or a combination of several of optical microscope removal, scanning electron microscope removal, dual beam electron microscope removal, transmission electron microscope removal.
29. The method according to claim 26, wherein in the step (b 1), the method of growing the single crystal comprises one or a combination of a plurality of evaporation method, a temperature reduction method and a diffusion method.
30. The method of claim 26, wherein in step (b 2), the collecting comprises employing one or a combination of several of optical microscopy, scanning electron microscopy, dual beam electron microscopy, transmission electron microscopy.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1092980A (en) * | 1992-07-31 | 1994-10-05 | 美国生物科学有限公司 | Crystallization D2EHDTPA dihydro S-2-(3-ammonia third amino) ethyl ester compositions and preparation and using method |
CN1297448A (en) * | 1998-04-25 | 2001-05-30 | 史密丝克莱恩比彻姆有限公司 | Paroxetine ascorbate |
CN101312744A (en) * | 2005-11-22 | 2008-11-26 | 惠氏公司 | Immunoglobulin fusion protein formulations |
CN101347412A (en) * | 2008-09-02 | 2009-01-21 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
CN102552149A (en) * | 2012-03-02 | 2012-07-11 | 海南灵康制药有限公司 | Calcium heparin liposome preparation for injection |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003296893A1 (en) * | 2003-01-15 | 2004-08-13 | Dow Global Technologies Inc. | Drug particles obtained by freezing onto a cold surface |
WO2009091053A1 (en) * | 2008-01-17 | 2009-07-23 | Sosho, Inc. | Crystal production method, frozen crystal production method, crystal, crystal structure analysis method, crystallization screening method, and crystallization screening apparatus |
CN101647783B (en) * | 2009-07-24 | 2010-12-22 | 上海复旦复华药业有限公司 | Prefreezing method in preparing injection-used reduced glutathione with freeze drying method |
CN102942576B (en) * | 2012-11-05 | 2015-01-28 | 海南卫康制药(潜山)有限公司 | New crystal form composition of cefminox sodium and preparation method thereof |
RU2530093C1 (en) * | 2013-05-15 | 2014-10-10 | Федеральное государственное автономное образовательное учреждение высшего образования "Новосибирский национальный исследовательский государственный университет" (Новосибирский государственный университет, НГУ) | Method of producing monocrystals of serotonin salts by crystallisation from aqueous solutions |
CN103951562B (en) * | 2014-05-09 | 2016-04-20 | 四川九章生物化工科技发展有限公司 | A kind of chlorogenic acid crystal formation and preparation method thereof |
CN104230808B (en) * | 2014-08-22 | 2016-05-18 | 苏州亚宝药物研发有限公司 | Amorphous ivabradine hydrochloride and preparation method thereof and application |
CN104387421B (en) * | 2014-11-27 | 2016-04-06 | 苏州二叶制药有限公司 | Adefovir ester monohydrate and preparation method thereof |
-
2019
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- 2019-10-29 CN CN201911039683.0A patent/CN110607554B/en active Active
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1092980A (en) * | 1992-07-31 | 1994-10-05 | 美国生物科学有限公司 | Crystallization D2EHDTPA dihydro S-2-(3-ammonia third amino) ethyl ester compositions and preparation and using method |
CN1297448A (en) * | 1998-04-25 | 2001-05-30 | 史密丝克莱恩比彻姆有限公司 | Paroxetine ascorbate |
CN101312744A (en) * | 2005-11-22 | 2008-11-26 | 惠氏公司 | Immunoglobulin fusion protein formulations |
CN101347412A (en) * | 2008-09-02 | 2009-01-21 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
CN102552149A (en) * | 2012-03-02 | 2012-07-11 | 海南灵康制药有限公司 | Calcium heparin liposome preparation for injection |
Non-Patent Citations (1)
Title |
---|
一种新型CPT非内酯环类似物的合成与晶体结构;卢雯等;《化学通报》;20130618(第06期);第527-531页 * |
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