CN115557867A - Disulfiram inclusion compound eutectic and preparation method and application thereof - Google Patents
Disulfiram inclusion compound eutectic and preparation method and application thereof Download PDFInfo
- Publication number
- CN115557867A CN115557867A CN202211316988.3A CN202211316988A CN115557867A CN 115557867 A CN115557867 A CN 115557867A CN 202211316988 A CN202211316988 A CN 202211316988A CN 115557867 A CN115557867 A CN 115557867A
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- Prior art keywords
- degrees
- disulfiram
- cyclodextrin
- crystal
- clathrate
- Prior art date
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- 229960002563 disulfiram Drugs 0.000 title claims abstract description 175
- 230000005496 eutectics Effects 0.000 title claims abstract description 66
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 61
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- C07C333/14—Dithiocarbamic acids; Derivatives thereof
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/32—Alcohol-abuse
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention provides a disulfiram inclusion compound eutectic, which comprises a eutectic ligand and a pharmaceutical active ingredient included by the eutectic ligand; the active ingredient of the medicine is disulfiram, and the eutectic ligand is cyclodextrin. The inclusion compound eutectic formed by the disulfiram and the cyclodextrin has better water solubility, better thermal stability and a more definite crystal structure. In addition, the preparation of the nanoparticles by the fusion solvent injection method and the crystallization by the anti-solvent method can be realized by combining proper heating temperature, and the preparation method is simple and easy to implement and is convenient to popularize and apply.
Description
Technical Field
The invention relates to the field of fine chemical engineering and application, in particular to a disulfiram clathrate eutectic and a preparation method and application thereof.
Background
Disulfiram is also called abstinence sulfur and disulfiram, is a common name of abstinence sulfur medicines and is a medicine for treatingA medicine for treating chronic alcoholism and alcoholism psychosis has been used in many countries as a medicine for abstinence of alcohol, and its molecular formula is C 10 H 20 N 2 S 4 And the molecular weight is 296.5. It has the functions of preventing liver from decomposing or metabolizing alcohol after drinking alcohol, and is taken orally once a day, so that even if a small amount of alcohol is drunk after the medicine is taken, the body can feel uncomfortable, and the aim of giving up alcohol is fulfilled. Disulfiram can be combined with an enzyme called acetaldehyde dehydrogenase, which plays an important role in the breakdown of alcohol. Without this enzyme, alcohol cannot be metabolized or eliminated as usual, resulting in discomfort or vomiting. Disulfiram drugs suffer from poor water solubility and are currently mainly formulated into inclusion compounds to increase their solubility in water. However, disulfiram inclusion compound has some disadvantages, such as the need to add several times of the inclusion agent during the preparation process, but the complete separation of the excess inclusion agent is not possible.
Cyclodextrins (CD) are a class of cyclic oligosaccharides produced by starch under the action of glucosyltransferases, which are typically produced by certain species of the genus Bacillus. The cyclodextrin has a stereo chiral cavity with inner hydrophobic and outer hydrophilic. The inner side of the cavity of the cyclodextrin structure consists of two circles of hydrogen atoms and one circle of oxygen atoms of glycosidic bonds and is under the shielding of C-H bonds, so that the inner cavity of the cyclodextrin is hydrophobic, and the outer side of the cyclodextrin molecule is hydrophilic due to the aggregation of hydroxyl groups. The cyclodextrin is composed of glucose, so the cyclodextrin has the characteristics of no toxicity, no harm, no side effect, capability of being absorbed by human bodies and the like, has the general property of starch, can be used as a filler and a binder of medicaments, and is widely applied in the fields of medicines, foods, chemical industry, materials, environmental protection, analytical chemistry and the like.
Disclosure of Invention
Based on the above, the invention provides a disulfiram clathrate eutectic which has better water solubility and better thermal stability, can improve bioavailability and has a definite crystal structure.
The invention is realized by the following technical scheme.
A disulfiram clathrate co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient included by the co-crystal ligand; the active ingredient of the medicine is disulfiram, and the eutectic ligand is cyclodextrin.
In one embodiment, the cyclodextrin is beta-cyclodextrin or gamma-cyclodextrin.
In one embodiment, the X-ray powder diffraction pattern of the disulfiram/β cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2 θ (°) angles:
6.6 degrees +/-0.2 degrees, 6.7 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 11.2 degrees +/-0.2 degrees, 11.6 degrees +/-0.5 degrees, 17.3 degrees +/-0.2 degrees, 17.7 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees and 23.8 degrees +/-0.2 degrees;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2 theta (°) angles:
7.4 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.4 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.4 degrees +/-0.2 degrees, 26.8 degrees +/-0.2 degrees and 34.9 degrees +/-0.2 degrees.
In one embodiment, the X-ray powder diffraction pattern of the disulfiram/β cyclodextrin inclusion compound co-crystal is substantially as shown in figure 5;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion compound co-crystal is substantially as shown in figure 5.
In one embodiment, the melting point of the disulfiram/beta cyclodextrin inclusion co-crystal is 251 ℃ ± 5 ℃;
the melting point of the disulfiram/gamma cyclodextrin inclusion compound eutectic is 209 ℃. + -. 5 ℃.
In one embodiment, in the disulfiram clathrate eutectic, the mass percentage of disulfiram in the disulfiram/beta cyclodextrin clathrate eutectic is 7.0% -9.0%;
in the disulfiram/gamma cyclodextrin inclusion compound eutectic, the mass percent of disulfiram is 9.2-11.2%.
The invention also provides a preparation method of the disulfiram clathrate eutectic, which comprises the following steps:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin water solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the disulfiram solution to prepare a mixed solution;
cooling the mixed solution, standing, and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
In one embodiment, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In one embodiment, the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).
In one embodiment, the molar ratio of the disulfiram to the cyclodextrin in the mixed solution is 1 (1-20).
In one embodiment, the adding of the disulfiram solution is performed by one or more of the following conditions:
(1) The adding time is controlled to be 0.5min to 30min based on 1mL to 5mL of the disulfiram solution;
(2) Stirring the cyclodextrin water solution at the rotating speed of 100 rpm-1000 rpm.
The invention also provides application of the disulfiram clathrate eutectic in preparation of chemical preparations, medicaments or foods.
Compared with the prior art, the disulfiram clathrate eutectic disclosed by the invention has the following beneficial effects:
the inclusion compound eutectic formed by disulfiram and cyclodextrin is obtained through research and preparation. Compared with the traditional inclusion compound, the eutectic of the inclusion compound formed by the disulfiram and the cyclodextrin has better water solubility, and the oral bioavailability of the disulfiram is improved; meanwhile, compared with disulfiram, the melting point of the clathrate eutectic is obviously increased, which shows that the thermal stability of the disulfiram/cyclodextrin clathrate eutectic is improved. In addition, clathrate co-crystals also have a more defined crystal structure. Different from the mode of forming crystals by utilizing hydrogen bonds, electrostatic interaction and the like between active ingredients of medicaments and eutectic ligands in the preparation of conventional eutectics, the clathrate compound eutectics provided by the invention utilize the characteristic that cyclodextrin and disulfiram can form an clathrate compound, and the cyclodextrin and the disulfiram are assembled by a host and an object to form the clathrate compound eutectics so as to increase the water solubility of the disulfiram.
Furthermore, the preparation of the nanoparticles by the fusion solvent injection method and the crystallization by the anti-solvent method can be realized by combining proper heating temperature, and the preparation method is simple and easy to implement and is convenient to popularize and apply.
Drawings
FIG. 1 is a schematic view of a preparation process of a disulfiram clathrate eutectic provided in the present invention;
FIG. 2 is an optical microscope photograph (scale: 50 μm) of a disulfiram/β cyclodextrin inclusion co-crystal and a disulfiram/γ cyclodextrin inclusion co-crystal according to the present invention;
FIG. 3 is an H-NMR spectrum of a disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta cyclodextrin inclusion co-crystal and disulfiram/gamma cyclodextrin inclusion co-crystal according to the present invention;
FIG. 4 is an infrared spectrum of a disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta cyclodextrin inclusion co-crystal and disulfiram/gamma cyclodextrin inclusion co-crystal provided in the present invention;
fig. 5 is an XPRD spectrum (the abscissa is an angle 2 θ (°), and the ordinate is intensity) of the disulfiram, β -cyclodextrin, γ -cyclodextrin, disulfiram/β -cyclodextrin inclusion co-crystal and disulfiram/γ -cyclodextrin inclusion co-crystal provided by the present invention;
fig. 6 is a DSC chart of disulfiram, β -cyclodextrin, γ -cyclodextrin, disulfiram/β -cyclodextrin inclusion compound co-crystals and disulfiram/γ -cyclodextrin inclusion compound co-crystals provided by the present invention (abscissa is temperature (deg.c), and ordinate is heat flow rate (W/g)).
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully hereinafter with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or to implicitly indicate the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless explicitly specified otherwise.
The words "preferably," "more preferably," and the like, in the context of the present invention, refer to embodiments of the invention that may, in some instances, provide certain benefits. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All qualities relating to the listed ingredients are given to the content of active substance, unless otherwise specified, and therefore they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percent content" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless otherwise indicated. All formulations and tests herein occur at 25 ℃ environment, unless otherwise indicated. The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass non-exclusive inclusions, as well as non-exclusive distinctions between such terms. The term "comprising" means that other steps and ingredients can be added which do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein. The terms "potency", "performance", "effect" and "efficacy" are not distinguished from one another herein.
"pharmaceutically acceptable" refers to those ligands, materials, compositions, and/or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and are commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and/or pharmacological effect, either in vivo or in vitro, and often provides a beneficial effect. The "drug" is not particularly limited in the range that produces physiological and/or pharmacological effects in vivo, and may be systemically or locally effective. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.
The dosage form and mode of administration of the compounds of the present invention or pharmaceutical compositions thereof are not particularly limited.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils, or mixtures of these materials. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. If suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium methoxide and agar, or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants. Is prepared by mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required if desired.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The invention provides a disulfiram inclusion compound eutectic, which comprises a eutectic ligand and a pharmaceutical active ingredient included by the eutectic ligand; the active ingredient of the medicine is disulfiram, and the eutectic ligand is cyclodextrin.
In a specific example, the cyclodextrin is β -cyclodextrin or γ -cyclodextrin.
In a specific example, the X-ray powder diffraction pattern of the disulfiram/β cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2 θ (°) angles:
6.6 degrees +/-0.2 degree, 6.7 degrees +/-0.2 degree, 9.9 degrees +/-0.2 degree, 11.2 degrees +/-0.2 degree, 11.6 degrees +/-0.5 degree, 17.3 degrees +/-0.2 degree, 17.7 degrees +/-0.2 degree, 19.9 degrees +/-0.2 degree, 20.3 degrees +/-0.2 degree and 23.8 degrees +/-0.2 degree
In a specific example, the X-ray powder diffraction pattern of the disulfiram/γ cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2 θ (°) angles:
7.4 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.4 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.4 degrees +/-0.2 degrees, 26.8 degrees +/-0.2 degrees and 34.9 degrees +/-0.2 degrees.
In a specific example, the X-ray powder diffraction pattern of the disulfiram/β cyclodextrin inclusion compound co-crystal is substantially as shown in fig. 5.
In a particular example, the X-ray powder diffraction pattern of the disulfiram/γ cyclodextrin inclusion compound co-crystal is substantially as shown in fig. 5.
In one particular example, the differential scanning calorimetry curve of the disulfiram/β cyclodextrin inclusion co-crystal is substantially as shown in fig. 6.
In a particular example, the differential scanning calorimetry curve of the disulfiram/γ cyclodextrin inclusion co-crystal is substantially as shown in fig. 6.
In a specific example, the melting point of the disulfiram/β cyclodextrin inclusion co-crystal is 251 ℃ ± 5 ℃.
It is understood that in the present invention, the melting point of the disulfiram/beta cyclodextrin inclusion co-crystal includes, but is not limited to 246 ℃, 247 ℃, 248 ℃, 249 ℃, 250 ℃, 251 ℃, 252 ℃, 253 ℃, 254 ℃, 255 ℃ or 256 ℃.
In a specific example, the melting point of the disulfiram/gamma cyclodextrin inclusion compound co-crystal is 209 ℃ ± 5 ℃.
It is understood that in the present invention, the melting point of the disulfiram/γ cyclodextrin inclusion co-crystal includes, but is not limited to, 204 ℃, 205 ℃, 206 ℃, 207 ℃,208 ℃, 209 ℃, 210 ℃, 211 ℃, 212 ℃, 213 ℃, or 214 ℃.
In a specific example, the weight percentage of disulfiram in the disulfiram/β cyclodextrin inclusion compound eutectic is 7.0% to 9.0%.
It is understood that in the present invention, the mass percentage of disulfiram in the disulfiram/β cyclodextrin inclusion co-crystal includes, but is not limited to, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%.
In a specific example, the weight percentage of the disulfiram in the disulfiram/gamma cyclodextrin inclusion compound eutectic is 9.2-11.2%.
It is understood that in the present invention, the mass percentage of disulfiram in the disulfiram/γ cyclodextrin inclusion compound eutectic includes, but is not limited to, 9.2%, 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%.
In one particular example, the crystals of the disulfiram clathrate co-crystal are in the form of a bulk.
In a specific example, the disulfiram clathrate eutectic size is between 10 μm and 20 μm.
With reference to fig. 1, the invention also provides a preparation method of the disulfiram clathrate eutectic, which comprises the following steps:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin water solution;
heating cyclodextrin water solution to 30-60 ℃, and then adding disulfiram solution to prepare mixed solution;
cooling the mixed solution, standing, and collecting precipitated solid;
wherein the first solvent is an organic solvent miscible with water.
The first solvent serves as a solvent for disulfiram, and can serve as a diluent and a transfer medium for the drug. After the disulfiram solution is injected into the aqueous solution of cyclodextrin, the solvent can be rapidly combined with water molecules, so that the dispersion of the disulfiram in water and the formation of an inclusion compound eutectic are promoted; on the other hand, the organic solvent can be used as a poor solvent of the cyclodextrin to promote the precipitation of the clathrate eutectic crystal from the solution.
In a specific example, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In a specific example, the volume ratio of the first solvent to water in the mixed solution is 3 (7 to 60).
In the present invention, the volume ratio of the first solvent to water includes, but is not limited to, 3.
More specifically, a fixed volume of disulfiram solution is injected into the aqueous cyclodextrin solution, and the ratio of organic solvent to water is controlled within a certain range, such as methanol to water = 1; ethanol: water = 1; acetonitrile, water = 1; acetone: water = 1; isopropanol-water = 1; ethylene glycol water = 1.
In a specific example, the molar ratio of disulfiram to cyclodextrin in the mixed solution is 1 (1-20).
Understandably, in the present invention, the molar ratio of disulfiram to cyclodextrin in the mixed solution includes but is not limited to 1.
In a specific example, the concentration of disulfiram in the disulfiram solution is 1mg/mL to 15mg/mL.
It is understood that in the present invention, the concentration of disulfiram in the disulfiram solution includes, but is not limited to, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 12mg/mL, 15mg/mL.
In a specific example, the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3mg/mL to 50mg/mL.
More specifically, in the beta-cyclodextrin aqueous solution, the concentration of the beta-cyclodextrin is 3 mg/mL-30 mg/mL. It is understood that, in the present invention, the concentration of beta-cyclodextrin in the aqueous solution of beta-cyclodextrin includes, but is not limited to, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 30mg/mL. Preferably, the concentration of beta-cyclodextrin is 10mg/mL.
It is understood that, in the present invention, the concentration of γ -cyclodextrin in the aqueous solution of γ -cyclodextrin includes, but is not limited to, 3mg/mL, 5mg/mL, 7mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL. Preferably, the concentration of the gamma-cyclodextrin in the gamma-cyclodextrin aqueous solution is 20mg/mL.
In a specific example, the adding time of the disulfiram solution is controlled to be 0.5-30 min based on 1-5 mL of the disulfiram solution.
It is understood that, in the present invention, the adding time of the disulfiram solution is controlled based on 1mL to 5mL of the disulfiram solution, including but not limited to 0.5min, 0.6min, 0.7min, 0.8min, 1min, 1.2min, 1.4min, 1.5min, 1.6min, 1.7min, 1.8min, 1.9min, 2min, 2.1min, 2.2min, 2.3min, 2.4min, 2.5min, 3min, 4min, 5min, 6min, 7min, 8min, 10min, 15min, 20min, 25min, 30min. Preferably, the time of addition is controlled to be 3min.
In a specific example, the aqueous cyclodextrin solution is stirred at a speed of 100rpm to 1000rpm during the addition of the disulfiram solution.
It is understood that the rotation speed of stirring the cyclodextrin aqueous solution during the addition of the disulfiram solution in the present invention includes, but is not limited to, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm.
In one specific example, the mixture is cooled to 4 ℃ to 30 ℃.
In a specific example, the mixture is allowed to stand for 4 to 72 hours.
In a specific example, the method further comprises the following steps after collecting the precipitated solid:
filtering the precipitated solid, washing the solid for 1 to 3 times by using ice water or a precooled crystallization solvent, and collecting a white solid; then the white solid is dried for 1 to 24 hours at the temperature of between 30 and 60 ℃.
The invention also provides application of the disulfiram inclusion compound eutectic in preparation of chemical preparations, medicaments or foods.
The disulfiram clathrate eutectic and the preparation method thereof of the present invention are further described in detail with reference to the following specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a disulfiram clathrate eutectic, which comprises the following specific preparation processes:
(1) Respectively preparing aqueous solution of beta-cyclodextrin and disulfiram solution. Wherein the disulfiram solvent is acetonitrile, the concentration of the acetonitrile is 3mg/mL, and the concentration of the beta-cyclodextrin is 15mg/mL.
(2) Heating the cyclodextrin aqueous solution to 50 deg.C; 1mL of disulfiram solution was added to 7mL of an aqueous cyclodextrin solution with stirring at 50rpm, and the addition time was controlled to 1 minute, and 2mL of acetonitrile was added and stirring was continued for 0.5 minute.
(3) Stopping heating and stirring, and cooling the mixed solution of disulfiram and cyclodextrin to 30 ℃; standing for 8 hr until the crystal precipitation is completed.
(4) Filtering to obtain white solid, washing with 4 deg.C water for 3 times; and then drying the product at 40 ℃ for 48 hours to obtain white powder which is an inclusion compound eutectic formed by the disulfiram and the cyclodextrin. The yield of the product is 80 percent based on disulfiram.
Example 2
The embodiment provides a disulfiram clathrate eutectic, which is prepared by the following specific steps:
(1) Respectively preparing an aqueous solution of the gamma-cyclodextrin and a disulfiram solution. Wherein the solvent of disulfiram is acetone with the concentration of 6mg/mL, and the concentration of gamma-cyclodextrin is 20mg/mL.
(2) Heating the cyclodextrin aqueous solution to 50 deg.C; 1mL of disulfiram solution was added to 7mL of aqueous cyclodextrin solution with stirring at 50rpm for 2 minutes, and 2mL of acetone was added and stirring was continued for 0.5 minute.
(3) Stopping heating and stirring, and cooling the mixed solution of disulfiram and cyclodextrin to 30 ℃; standing for 8 hr until the crystal precipitation is completed.
(4) Filtering to obtain white solid, washing with 4 deg.C water for 3 times; and then drying the product at 40 ℃ for 48 hours to obtain white powder which is an inclusion compound eutectic formed by disulfiram and cyclodextrin. The yield of the product is 85 percent based on disulfiram.
Comparative example 1
This comparative example provides a preparation method of trying to prepare a β -cyclodextrin crystal, specifically as follows:
(1) Preparing an aqueous solution of beta-cyclodextrin, wherein the concentration of the beta-cyclodextrin is 15mg/mL.
(2) The aqueous cyclodextrin solution was heated to 50 ℃.
(3) Stopping heating, and cooling the cyclodextrin water solution to 30 ℃; after standing for 8 hours, no solid precipitated.
Comparative example 2
This comparative example provides a method of attempting to prepare a gamma-cyclodextrin crystal, as follows:
(1) Preparing an aqueous solution of the gamma-cyclodextrin, wherein the concentration of the gamma-cyclodextrin is 20mg/mL.
(2) The aqueous cyclodextrin solution was heated to 50 ℃.
(3) Stopping heating, and cooling the cyclodextrin water solution to 30 ℃; after standing for 8 hours, no solid precipitated.
The disulfiram clathrate co-crystal prepared in example 1 was characterized by crystal morphology, H-NMR, infrared spectroscopy, X-ray powder diffraction (XRD) and Differential Scanning Calorimetry (DSC), and the results are as follows:
(1) Morphology of crystal
The clathrate eutectic prepared in example 1 and example 2 above was placed on a slide glass, and the morphology of each sample was observed and recorded under an optical microscope (10 × 20), and the results are shown in fig. 2: the eutectic formed by the disulfiram and the cyclodextrin has definite crystal habit, and the eutectic of the disulfiram/beta cyclodextrin and the disulfiram/gamma cyclodextrin presents transparent bulk crystals with the size of about 10-20 mu m.
(2)H-NMR
Disulfiram, beta-cyclodextrin, gamma-cyclodextrin and the inclusion compound co-crystals prepared in example 1-2 above were used in the preparation of d 6 The hydrogen spectra were determined after the DMSO dissolution, and the results are shown in FIG. 3. The H-NMR data of the disulfiram/beta cyclodextrin inclusion compound eutectic simultaneously contain signals of disulfiram and beta cyclodextrin, and the crystal is confirmed to be composed of two components; the H-NMR data of the disulfiram/gamma cyclodextrin inclusion compound eutectic simultaneously contain signals of disulfiram and gamma cyclodextrin, and the crystal is confirmed to be composed of two components.
(3) Infrared spectroscopy
The IR spectra of disulfiram, beta-cyclodextrin, gamma-cyclodextrin and the inclusion compound co-crystal prepared in example 1-2 are shown in FIG. 4. Wherein the characteristic peak of disulfiram is 910cm -1 、964cm -1 、1192cm -1 、1270cm -1 、1347cm -1 、1375cm -1 、1415cm -1 、1494cm -1 Etc.; the characteristic peak of cyclodextrin is 400-2000cm -1 To (c) to (d); compared with the raw materials, most of characteristic peaks related to disulfiram in the infrared spectrum of the disulfiram/beta cyclodextrin and disulfiram/gamma cyclodextrin inclusion compound eutectic disappear, the infrared spectrum of the disulfiram/beta cyclodextrin and disulfiram/gamma cyclodextrin inclusion compound eutectic is consistent with that of cyclodextrin on the whole, and the result shows that the medicament and the cyclodextrin form an inclusion compound, so the characteristic peaks of disulfiram in the structure are covered by the cyclodextrin.
(4)XRD
The XPRD patterns of disulfiram, beta-cyclodextrin, gamma-cyclodextrin and the inclusion co-crystals prepared in examples 1-2 above are shown in fig. 5. The characteristic peaks of the disulfiram crystals are 9.8 degrees, 11.7 degrees, 13.9 degrees, 14.4 degrees, 17.4 degrees, 19.5 degrees, 21.3 degrees, 24.7 degrees, 25.7 degrees, 29.8 degrees, 33.1 degrees and 40.4 degrees, the XRD diffraction peaks of the disulfiram/beta cyclodextrin eutectic are 6.6 degrees, 6.7 degrees, 9.9 degrees, 11.2 degrees, 11.6 degrees, 17.3 degrees, 17.7 degrees, 19.9 degrees, 20.3 degrees and 23.8 degrees, and the XRD diffraction peaks of the disulfiram/gamma cyclodextrin eutectic are 7.4 degrees, 11.5 degrees, 11.7 degrees, 12.0 degrees, 12.6 degrees, 14.2 degrees, 14.9 degrees, 15.8 degrees, 16.6 degrees, 19.2 degrees, 20.3 degrees, 20.4 degrees, 21.1 degrees, 21.8 degrees, 22.4 degrees, 23.6 degrees, 24.2 degrees, 25.4 degrees, 26.8 degrees and 34.9 degrees. The characteristic diffraction peak of XPRD of the product prepared in the above example 1-2 is completely different from that of the raw material, which shows that the crystal forms a new crystal form instead of simple physical mixing, and HNMR results show that the crystal simultaneously contains cyclodextrin and disulfiram, so that the crystal can be determined as a disulfiram/beta cyclodextrin eutectic and a disulfiram/gamma cyclodextrin eutectic.
(5)DSC
DSC spectra (heating rate by DSC: 10K/min) of disulfiram, beta-cyclodextrin, gamma-cyclodextrin and the clathrate co-crystal prepared in the above example 1-2 are shown in FIG. 6. The onset point of disulfiram is 67.2 ℃, and after the disulfiram forms a eutectic with cyclodextrin, the melting points of the inclusion compound eutectic are 251.3 ℃ (disulfiram/beta cyclodextrin eutectic) and 208.9 ℃ (disulfiram/gamma cyclodextrin eutectic), respectively, and the result shows that the heat stability of the disulfiram is obviously improved after the disulfiram forms the inclusion compound eutectic.
Solubility determination experiments were performed on disulfiram in a co-crystal with the clathrate prepared in example 1-2 above, with the following results:
the cyclodextrin inclusion compound eutectic obviously improves the solubility of the drug in water. Disulfiram is almost insoluble in water and has a solubility of about 4 mug/mL, while the solubilities of the two clathrate eutectics in water are respectively 400 mug/mL (disulfiram/beta cyclodextrin eutectics) and 100 mug/mL (disulfiram/gamma cyclodextrin eutectics), which are increased by 40 times and 25 times, and the water solubility is obviously increased.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.
Claims (12)
1. A disulfiram clathrate co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient included by the co-crystal ligand; the active ingredient of the medicine is disulfiram, and the eutectic ligand is cyclodextrin.
2. The disulfiram inclusion co-crystal of claim 1, wherein the cyclodextrin is β -cyclodextrin or γ -cyclodextrin.
3. The disulfiram clathrate co-crystal of claim 2, wherein the disulfiram/β cyclodextrin clathrate co-crystal has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ (°) angles:
6.6 degrees +/-0.2 degrees, 6.7 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 11.2 degrees +/-0.2 degrees, 11.6 degrees +/-0.5 degrees, 17.3 degrees +/-0.2 degrees, 17.7 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees and 23.8 degrees +/-0.2 degrees;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2 theta (°) angles:
7.4 degrees +/-0.2 degrees, 11.5 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.6 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 15.8 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 21.8 degrees +/-0.2 degrees, 22.4 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 24.2 degrees +/-0.2 degrees, 25.4 degrees +/-0.2 degrees, 26.8 degrees +/-0.2 degrees and 34.9 degrees +/-0.2 degrees.
4. The disulfiram clathrate co-crystal of claim 2, wherein the disulfiram/β cyclodextrin clathrate co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 5;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion compound co-crystal is substantially as shown in figure 5.
5. The disulfiram clathrate co-crystal of claim 2, wherein the disulfiram/β cyclodextrin clathrate co-crystal has a melting point of 251 ℃ ± 5 ℃;
the melting point of the disulfiram/gamma cyclodextrin inclusion compound eutectic is 209 ℃. + -. 5 ℃.
6. The disulfiram clathrate co-crystal of claim 2, characterized in that the disulfiram/β cyclodextrin clathrate co-crystal has a mass percent of disulfiram of 7.0% to 9.0%;
in the disulfiram/gamma cyclodextrin inclusion compound eutectic, the mass percent of disulfiram is 9.2-11.2%.
7. A process for the preparation of a disulfiram clathrate co-crystal as defined in any one of claims 1 to 6 comprising the steps of:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin water solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the disulfiram solution to prepare a mixed solution;
cooling the mixed solution, standing, and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
8. The method of preparing a disulfiram clathrate co-crystal of claim 7, wherein the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol and ethylene glycol.
9. The method of claim 7, wherein the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).
10. The method of claim 7, wherein the molar ratio of disulfiram to cyclodextrin in the mixture is 1 (1-20).
11. The process for the preparation of a disulfiram clathrate co-crystal according to any one of claims 7 to 10, characterized in that the addition of the disulfiram solution is performed in one or more of the following conditions:
(1) Controlling the adding time to be 0.5-30 min based on 1-5 mL of the disulfiram solution;
(2) Stirring the cyclodextrin water solution at the rotating speed of 100 rpm-1000 rpm.
12. Use of the disulfiram clathrate co-crystal of any one of claims 1 to 6 in the manufacture of a chemical formulation, a medicament or a food product.
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