CN115650993B - Clopidogrel Lei Baoge cocrystal, pharmaceutical composition, and preparation methods and application thereof - Google Patents

Abstract

The invention provides clopidogrel inclusion compound eutectic, which comprises a eutectic ligand and a medicine active ingredient which is included by the eutectic ligand; the active component of the medicine is clopidogrel, and the eutectic ligand is cyclodextrin, in particular gamma cyclodextrin. The inclusion compound eutectic formed by clopidogrel and gamma cyclodextrin has better water solubility, higher melting point, better stability and more definite crystal structure. In addition, the preparation method of the inclusion compound eutectic formed by clopidogrel and cyclodextrin can be realized by combining proper heating temperature through the preparation method of nanoparticles by a fusion solvent injection method and crystallization by an anti-solvent method, and is simple and feasible, and convenient to popularize and apply.

Description

Clopidogrel Lei Baoge cocrystal, pharmaceutical composition, and preparation methods and application thereof

Technical Field

The invention relates to the fields of fine chemical engineering and application, in particular to clopidogrel inclusion compound eutectic crystal, a pharmaceutical composition, a preparation method and application thereof.

Background

Clopidogrel is a thienopyridine antiplatelet agent for preventing thrombosis of peripheral vascular disease, coronary artery disease and cerebrovascular disease, and has a molecular formula of C ₁₆ H ₁₈ ClNO ₆ S ₂ The molecular weight is 419.91. Clopidogrel is hardly dissolved in water, and clopidogrel has a problem of poor stability due to an unstable proton in a chiral center in a molecular structure, easy racemization and easy hydrolysis of methyl ester groups. Antioxidants do not prevent thisSeed degradation, while higher pH values further enhance clopidogrel instability, suggests clopidogrel should be more stable in theory in salt formation with acids. However, clopidogrel is not easily formed into a solid salt with conventional acids, and clopidogrel in the form of a bisulfate salt is prepared by the conventional method, which is also the most common salt-forming form of clopidogrel on the market.

Clopidogrel bisulfate is white to off-white powder, is easily dissolved in methanol, is slightly dissolved in dichloromethane, is insoluble in heptane and diethyl ether, is a polymorphic compound, and 7 reported crystal forms are available, wherein 5 crystal forms can wrap a solvent, so that the toxic and side effects of the product are increased, and the clopidogrel bisulfate is not easy to take medicine. At the same time, clopidogrel in the bisulfate form is not stable enough to avoid degradation and racemization of clopidogrel to the maximum extent.

Cyclodextrins (CD) are a class of cyclic oligosaccharides produced from starch by the action of a glycosyltransferase, which is typically produced by certain species of the genus Bacillus. The cyclodextrin has a three-dimensional chiral cavity with an inner hydrophobic and an outer hydrophilic. The inner side of the cavity of the cyclodextrin structure is composed of two circles of hydrogen atoms and one circle of oxygen atoms of the glycosidic bond, which are under the shielding of the C-H bond, 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 that 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 medicines, and is widely applied to the fields of medicines, foods, chemical engineering, materials, environmental protection, analytical chemistry and the like.

Disclosure of Invention

Based on the above, the clopidogrel inclusion compound eutectic is provided, and has better water solubility and higher melting point, better stability and definite crystal structure compared with clopidogrel raw materials.

The invention is realized by the following technical scheme.

A clopidogrel inclusion co-crystal comprising a co-crystal ligand and a pharmaceutically active ingredient that is included by the co-crystal ligand; the active component of the medicine is clopidogrel, and the eutectic ligand is cyclodextrin.

In one embodiment, the cyclodextrin is gamma-cyclodextrin.

In one embodiment, the clopidogrel/gamma cyclodextrin inclusion co-crystal has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ (°) angles:

5.751 ° ± 0.5 °, 5.986 ° ± 0.5 °, 7.572 ±0.5°, 10.098 ° ± 0.5 °, 10.502 ° ± 0.5 °, 11.724 ° ± 0.5 °, 13.946 ° ± 0.5 °, 15.553 ° ± 0.5 °, 16.055 ° ± 0.5 °, 17.561 ° ± 0.5 °, 19.622 ° ± 0.5 °, 21.246 ° ± 0.5 °, 21.831 ° ± 0.5 °, 23.453 ° ± 0.5 ° and 34.783 ° ± 0.5 °.

In one embodiment, the clopidogrel/gamma cyclodextrin inclusion co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 5.

In one embodiment, the clopidogrel/gamma cyclodextrin inclusion co-crystal has a melting point of 329 ℃ ± 5 ℃.

In one embodiment, the clopidogrel inclusion compound eutectic is 18.5-20.5% by mass of clopidogrel.

The invention also provides a preparation method of the clopidogrel inclusion compound eutectic, which comprises the following steps:

mixing clopidogrel with a first solvent to prepare a clopidogrel solution;

mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;

heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the clopidogrel Lei Rongye 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 clopidogrel to cyclodextrin in the mixed solution is 1 (1-20).

In one embodiment, the process of adding the clopidogrel Lei Rongye satisfies one or more of the following conditions:

(1) The adding time is controlled to be 0.5 to 30 minutes according to 1 to 3mL of clopidogrel Lei Rongye;

(2) The aqueous cyclodextrin solution is stirred at a speed of 50rpm to 1000rpm.

The invention also provides an antiplatelet pharmaceutical composition, which comprises clopidogrel inclusion compound eutectic as described above and a carrier or an auxiliary material.

The invention also provides application of the clopidogrel inclusion compound eutectic in preparing chemical preparations, medicines or foods.

Compared with the prior art, the clopidogrel Lei Baoge eutectic has the following beneficial effects:

according to the invention, the inclusion compound eutectic formed by clopidogrel and cyclodextrin is obtained through research and preparation. Compared with the traditional inclusion compound, the inclusion compound eutectic formed by clopidogrel and cyclodextrin has better water solubility, and meanwhile, compared with clopidogrel, the melting point of the inclusion compound eutectic is obviously increased, which indicates that the thermal stability of the clopidogrel/cyclodextrin inclusion compound eutectic is improved. In addition, after the clopidogrel is solidified through inclusion eutectic, the stability is obviously improved, and the degradation rate is lower than 5% in 30 days at 25 ℃ and lower than 10% at 60 ℃. Clopidogrel/cyclodextrin inclusion eutectic also has a more definite crystal structure, and particularly presents a transparent block shape. Unlike the conventional eutectic preparation in which crystals are formed by utilizing the hydrogen bond, electrostatic action and the like between the active pharmaceutical ingredient and the eutectic ligand, the inclusion compound eutectic of the invention utilizes the characteristic that cyclodextrin and clopidogrel can form inclusion compound, and the cyclodextrin and clopidogrel are assembled by a host and guest to form inclusion compound eutectic so as to increase the water solubility of clopidogrel.

Furthermore, the method for preparing nanoparticles by the fusion solvent injection method and crystallizing by the anti-solvent method can realize the preparation of inclusion compound eutectic formed by clopidogrel and cyclodextrin by combining proper heating temperature, and can be used as an intermediate raw material of clopidogrel for preparing various preparation forms such as solid, semisolid and the like. The preparation method of the invention is simple and feasible, and is convenient for popularization and application.

Drawings

Fig. 1 is a schematic diagram of a preparation process of clopidogrel inclusion compound eutectic provided by the invention;

fig. 2 is an optical micrograph of clopidogrel eutectic with clopidogrel Lei Baoge provided by the invention (clopidogrel scale: 50 μm, clopidogrel inclusion eutectic scale: 100 μm);

FIG. 3 is an H-NMR spectrum of clopidogrel, gamma-cyclodextrin, and clopidogrel/gamma-cyclodextrin inclusion eutectic provided by the invention; wherein, gamma CD-DMSO represents gamma-cyclodextrin, grel-DMSO represents clopidogrel, and gamma CD-Grel-DMSO represents clopidogrel/gamma cyclodextrin inclusion compound eutectic;

fig. 4 is an infrared spectrogram of clopidogrel, gamma-cyclodextrin and clopidogrel/gamma-cyclodextrin inclusion compound eutectic provided by the invention;

FIG. 5 is a XPRD spectrum (abscissa is angle 2 θ (°), and ordinate is intensity) of a gamma-cyclodextrin and clopidogrel/gamma cyclodextrin inclusion compound co-crystal provided by the invention;

FIG. 6 is a DSC graph (abscissa is temperature (. Degree. C.), and ordinate is heat rate (W/g)) of the co-crystal of gamma-cyclodextrin and clopidogrel/gamma-cyclodextrin inclusion compound provided by the invention;

fig. 7 is a content change chart and a degradation trend chart of clopidogrel/gamma cyclodextrin inclusion compound eutectic provided by the invention at 25 ℃ and 60 ℃.

Detailed Description

In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. 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 the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise. In the description of the present invention, the meaning of "several" means at least one, such as one, two, etc., unless specifically defined otherwise.

The words "preferably," "more preferably," and the like in the present invention refer to embodiments of the invention that may provide certain benefits in some instances. 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, nor is it 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 for 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 description 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 include 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 of the mass of the ingredients listed, unless otherwise indicated, are given to the active substance content and therefore they do not include solvents or by-products that may be included in commercially available materials. The term "mass percent" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless indicated otherwise. All formulations and tests herein take place in an environment of 25 ℃, unless otherwise indicated. The terms "comprising," "including," "containing," "having," or other variations thereof herein are intended to cover a non-closed inclusion, without distinguishing between them. The term "comprising" means that other steps and ingredients may be added that 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 additional or optional ingredients, components, steps, or limitations of any of the embodiments described herein. The terms "efficacy," "performance," "effect," "efficacy" are not differentiated herein.

By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and 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 compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious 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 in vivo or in vitro, and often provides a beneficial effect. The range of physiological and/or pharmacological actions of the "drug" in vivo is not particularly limited, and may be systemic or local. The activity of the "drug" is not particularly limited, and may be an active substance capable of interacting with other substances or an inert substance which does not interact with other substances.

The dosage form and the mode of administration of the compound of the present invention or the pharmaceutical composition 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, 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 substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous 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 excipients 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 aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.

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. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

The invention provides clopidogrel inclusion compound eutectic, which comprises a eutectic ligand and a medicine active ingredient which is included by the eutectic ligand; the active component of the medicine is clopidogrel, and the eutectic ligand is cyclodextrin.

In one specific example, the cyclodextrin is gamma-cyclodextrin.

In a specific example, the X-ray powder diffraction pattern of clopidogrel/gamma cyclodextrin inclusion co-crystals has characteristic diffraction peaks at the following 2θ (°) angles:

5.751 ° ± 0.5 °, 5.986 ° ± 0.5 °, 7.572 ±0.5°, 10.098 ° ± 0.5 °, 10.502 ° ± 0.5 °, 11.724 ° ± 0.5 °, 13.946 ° ± 0.5 °, 15.553 ° ± 0.5 °, 16.055 ° ± 0.5 °, 17.561 ° ± 0.5 °, 19.622 ° ± 0.5 °, 21.246 ° ± 0.5 °, 21.831 ° ± 0.5 °, 23.453 ° ± 0.5 ° and 34.783 ° ± 0.5 °.

In one specific example, the clopidogrel/gamma cyclodextrin inclusion co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 5.

In one specific example, the differential scanning calorimetric curve of clopidogrel/gamma cyclodextrin inclusion co-crystals is substantially as shown in fig. 6.

In a specific example, the clopidogrel-gamma cyclodextrin inclusion co-crystal has a melting point of 329 ℃ ± 5 ℃.

It is understood that clopidogrel/gamma cyclodextrin inclusion eutectic has a melting point of 324 ℃, 325 ℃, 326 ℃, 327 ℃, 328 ℃, 329 ℃, 330 ℃, 331 ℃, 332 ℃, 333 ℃, 334 ℃.

In a specific example, the clopidogrel inclusion compound eutectic is 18.5-20.5% by mass of clopidogrel.

It is understood that in the present invention, clopidogrel Lei Baoge co-crystals include, but are not limited to, 18.5%, 18.7%, 18.9%, 19.0%, 19.2%, 19.4%, 19.6%, 19.8%, 20.0%, 20.2%, 20.4%, 20.5% by mass of clopidogrel.

In a specific example, clopidogrel inclusion eutectic crystals are in the form of a block.

In a specific example, clopidogrel inclusion has a eutectic size of 20 μm to 50 μm.

The invention also provides a preparation method of the clopidogrel inclusion compound eutectic, which comprises the following steps of:

mixing clopidogrel with a first solvent to prepare a clopidogrel solution;

mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;

heating cyclodextrin water solution to 30-60 ℃, and then adding clopidogrel solution to prepare mixed solution;

cooling the mixed solution, standing, and collecting precipitated solid;

wherein the first solvent is a water-miscible organic solvent.

The first solvent serves as a solvent for clopidogrel on the one hand and can serve as a diluent and a delivery medium for medicaments. After the clopidogrel solution is injected into the cyclodextrin aqueous solution, the solvent can be quickly combined with water molecules, so that the clopidogrel dispersion in water and the formation of inclusion compound eutectic are promoted; on the other hand, the organic solvent can be used as a poor solvent of cyclodextrin to promote the precipitation of inclusion compound eutectic 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).

It is understood that in the present invention, the volume ratio of the first solvent to water in the mixed liquor includes, but is not limited to, 3:7, 3:8, 3:9, 3:10, 3:11, 3:12, 3:13, 3:14, 3:15, 3:20, 3:25, 3:30, 3:35, 3:40, 3:45, 3:50, 3:55, 3:60.

More specifically, a fixed volume of clopidogrel solution is injected into cyclodextrin aqueous solution, and the ratio of organic solvent to water is controlled within a certain range, such as methanol: water=1:20-3:7; ethanol: water=1:20-3:7; acetonitrile: water=1:20-3:7; acetone: water=1:20-3:7; isopropanol: water=1:20-3:7; ethylene glycol water=1:20-3:7, and when clopidogrel solvent is insufficient, a blank solvent can be used to complement the ratio of solvent to water.

In a specific example, the molar ratio of clopidogrel to cyclodextrin in the mixed solution is 1 (1-20).

It is understood that in the present invention, the molar ratio of clopidogrel to cyclodextrin in the mixed liquor includes, but is not limited to, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20.

In a specific example, clopidogrel is present in a concentration of 1mg/mL to 10mg/mL in clopidogrel Lei Rongye.

It is understood that in the present invention, clopidogrel Lei Rongye, clopidogrel concentration 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.

In a specific example, the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3mg/mL to 50mg/mL. More specifically, in the aqueous solution of gamma-cyclodextrin, the concentration of gamma-cyclodextrin is 3 mg/mL-30 mg/mL. It will be appreciated that in the present invention, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution 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. Preferably, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution is 7mg/mL.

In a specific example, in the process of adding clopidogrel solution, the adding time is controlled to be 0.5 min-30 min according to 1 mL-3 mL of clopidogrel Lei Rongye.

It is understood that in the present invention, the time of controlling the addition includes, but is 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, based on 1mL to 3mL of the clopidogrel solution. Preferably, the addition time is controlled to be 3 minutes.

In a specific example, during the addition of the clopidogrel solution, the aqueous cyclodextrin solution is stirred at a rotational speed of 50rpm to 1000rpm.

It is understood that in the present invention, the rotational speed of stirring the aqueous cyclodextrin solution during the addition of clopidogrel solution includes, but is not limited to, 50rpm, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm.

In a specific example, the mixture is cooled to 4-30 ℃.

In one specific example, the mixture is left 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 precooled crystallization solvent, and collecting white solid; and then the white solid is dried for 1 to 24 hours at the temperature of between 30 and 60 ℃.

The invention also provides an antiplatelet pharmaceutical composition, which comprises the clopidogrel inclusion compound eutectic and a carrier or an auxiliary material.

In a specific example, the carrier or adjuvant is a pharmaceutically acceptable carrier or pharmaceutically acceptable adjuvant.

The invention also provides application of the clopidogrel inclusion compound eutectic in preparing chemical preparations, medicaments or foods.

The clopidogrel inclusion eutectic and the preparation method thereof of the present invention are described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.

Example 1

The embodiment provides clopidogrel inclusion compound eutectic, which is prepared by the following steps:

(1) Respectively preparing an aqueous solution of gamma-cyclodextrin and a clopidogrel solution. Wherein the clopidogrel solvent is ethanol with the concentration of 1mg/mL and the gamma-cyclodextrin with the concentration of 7mg/mL.

(2) Heating the cyclodextrin aqueous solution to 50 ℃; 1mL of clopidogrel solution was poured into 7mL of cyclodextrin aqueous solution under stirring at 50rpm, the addition time was controlled to be 1 minute, 2mL of acetone was additionally added, and stirring was continued for 0.5 minute.

(3) Stopping heating and stirring, and cooling the mixed solution of clopidogrel and cyclodextrin to 30 ℃; standing for 4 hours until crystals in the solution are completely separated out.

(4) Suction filtration to obtain white solid, washing 3 times with water at 4 ℃; and then drying the product at 40 ℃ for 48 hours to obtain the white powder which is the inclusion compound eutectic formed by clopidogrel and gamma-cyclodextrin. The yield of the product is 70 percent based on clopidogrel.

Comparative example 1

This comparative example provides a preparation method for attempting to prepare gamma-cyclodextrin crystals, specifically as follows:

(1) An aqueous solution of gamma-cyclodextrin was prepared, wherein the concentration of gamma-cyclodextrin was 7mg/mL.

(2) The cyclodextrin aqueous solution was heated to 50 ℃.

(3) Stopping heating, and cooling the cyclodextrin water solution to 30 ℃; after standing for 4 hours, no solid precipitated.

The clopidogrel Lei Baoge co-crystal prepared in the above example 1 was characterized, including crystal morphology, H-NMR, infrared spectrum, X-ray powder diffraction (XRD) and Differential Scanning Calorimeter (DSC), and the characterization results are specifically as follows:

(1) Crystal morphology

The inclusion compound eutectic prepared in the above example 1 is placed on a glass slide and placed on the glass slide, and the morphology of each sample is observed and recorded under an optical microscope (10×20); another 1mL of clopidogrel in methanol (3 mg/mL) was dispersed in 10mL of water, and after stirring well, a drop of the solution was placed on a slide glass as a control. The results are shown in FIG. 2: clopidogrel is dissolved in a good solvent and then injected into water, and can be dispersed in water to form droplets with a size of 2-3 μm. In contrast, clopidogrel, when added directly to water, forms oil droplets that are difficult to disperse. It can be seen that the water-miscible solvent is used as a medium to promote the existence of the drug in a monomolecular state in water, thereby effectively promoting the formation of inclusion compounds. In contrast to clopidogrel Lei Duizhao, the co-crystal formed by clopidogrel and gamma-cyclodextrin has a definite crystal habit: the crystal is transparent and has a size of about 20-50 μm.

(2)H-NMR

D for eutectic inclusion compound prepared in the above example 1 by clopidogrel and gamma-cyclodextrin ₆ Hydrogen spectra were determined after DMSO dissolution and the results are shown in figure 3. The H-NMR data of the co-crystal contains signals of clopidogrel and gamma-cyclodextrin at the same time, and the crystal is proved to be composed of two components.

(3) Infrared spectrum

The infrared spectra of clopidogrel, gamma-cyclodextrin and the inclusion compound eutectic prepared in the above example 1 are shown in fig. 4. Wherein the characteristic peak of clopidogrel is 700cm ^-1 、751cm ^-1 、1017cm ^-1 、1126cm ^-1 、1161cm ^-1 、1197cm ^-1 、1431cm ^-1 、1735cm ^-1 The method comprises the steps of carrying out a first treatment on the surface of the Cyclodextrin has characteristic peak of 400-2000cm ^-1 Between them; compared with the two, most of characteristic peaks of Guan Lvbi gray in the infrared spectrum of the inclusion compound eutectic formed by clopidogrel and gamma-cyclodextrin disappear, and the infrared spectrum is consistent with the gamma-cyclodextrin as a whole, which indicates that the medicament and the gamma-cyclodextrin form an inclusion compound, so that the characteristic peaks of clopidogrel in the structure are covered by the gamma-cyclodextrin.

(4)XRD

The XPRD of clopidogrel, gamma-cyclodextrin and the inclusion compound eutectic prepared in the above example 1 is shown in FIG. 5. Wherein the XRD diffraction peaks of the inclusion compound co-crystals prepared in example 1 above are 5.751 °, 5.986 °, 7.572, 10.098 °, 10.502 °, 11.724 °, 13.946 °, 15.553 °, 16.055 °, 17.561 °, 19.622 °, 21.246 °, 21.831 °, 23.453 ° and 34.783 °. The characteristic diffraction peak of the crystal XPRD is completely different from that of gamma-cyclodextrin, which indicates that the crystal XPRD is not simply physically mixed, but forms a new crystal form, and HNMR results show that the crystal contains gamma-cyclodextrin and clopidogrel to form at the same time, thus being identified as clopidogrel/gamma-cyclodextrin eutectic.

(5)DSC

The DSC spectrum (the temperature rise rate measured by DSC is 10K/min) of clopidogrel, gamma-cyclodextrin and the inclusion compound eutectic prepared in the above example 1 is shown in FIG. 6. Clopidogrel is a yellow transparent oily substance at room temperature, after the clopidogrel forms eutectic with gamma-cyclodextrin, the melting point of clopidogrel/gamma-cyclodextrin inclusion compound eutectic is 328.97 ℃, and the result shows that the thermal stability of clopidogrel after forming inclusion compound eutectic is obviously improved.

Solubility measurement experiments are carried out on clopidogrel and the clopidogrel-gamma cyclodextrin inclusion compound eutectic prepared in the embodiment 1, and the results are as follows:

the clopidogrel/gamma cyclodextrin inclusion compound eutectic prepared in example 1 improves the solubility of the drug in water. Clopidogrel free base is hardly soluble (< 1 μg/mL) in water, whereas clopidogrel/gamma cyclodextrin inclusion eutectic is about 30 μg/mL in water, and water solubility is significantly increased.

The stability of clopidogrel/gamma cyclodextrin inclusion compound co-crystal prepared in example 1 above under the storage conditions of 25 ℃ and 60 ℃ was examined, and the results are shown in fig. 7: after clopidogrel is solidified by a eutectic technology, an accelerated stability experiment result shows that the degradation rate of clopidogrel/gamma cyclodextrin inclusion compound eutectic is lower than 5% in 30 days at 25 ℃ and lower than 10% at 60 ℃, so that the stability of clopidogrel is obviously improved, and the clopidogrel inclusion compound eutectic has better stability.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.

Claims (12)

1. A clopidogrel inclusion co-crystal, comprising a co-crystal ligand and a pharmaceutically active ingredient that is included by the co-crystal ligand; the active component of the medicine is clopidogrel, and the eutectic ligand is cyclodextrin;

the clopidogrel inclusion eutectic X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ (°) angles:

5.751 ° ± 0.5 °, 5.986 ° ± 0.5 °, 7.572 ±0.5°, 10.098 ° ± 0.5 °, 10.502 ° ± 0.5 °, 11.724 ° ± 0.5 °, 13.946 ° ± 0.5 °, 15.553 ° ± 0.5 °, 16.055 ° ± 0.5 °, 17.561 ° ± 0.5 °, 19.622 ° ± 0.5 °, 21.246 ° ± 0.5 °, 21.831 ° ± 0.5 °, 23.453 ° ± 0.5 ° and 34.783 ° ± 0.5 °.

2. Clopidogrel inclusion co-crystal according to claim 1, wherein the cyclodextrin is gamma-cyclodextrin.

3. The clopidogrel clathrate co-crystal of claim 2, wherein an X-ray powder diffraction pattern of the clopidogrel/gamma cyclodextrin clathrate co-crystal is substantially as shown in fig. 5.

4. Clopidogrel inclusion co-crystal according to claim 2, characterized in that the melting point of clopidogrel/gamma cyclodextrin inclusion co-crystal is 329 ℃ ± 5 ℃.

5. The clopidogrel inclusion co-crystal of any one of claims 1 to 4, wherein the clopidogrel inclusion co-crystal comprises 18.5% to 20.5% by mass of clopidogrel.

6. A method for preparing clopidogrel inclusion co-crystal according to any one of claims 1 to 5, comprising the steps of:

mixing clopidogrel with a first solvent to prepare a clopidogrel solution;

mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;

heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the clopidogrel Lei Rongye to prepare a mixed solution;

cooling the mixed solution, standing and collecting precipitated solid;

wherein the first solvent is a water-miscible organic solvent.

7. The method for preparing clopidogrel inclusion compound co-crystal according to claim 6, wherein the first solvent is one or more selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol and ethylene glycol.

8. The method for preparing clopidogrel inclusion compound co-crystal according to claim 6, wherein the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).

9. The method for preparing clopidogrel inclusion compound co-crystal according to claim 6, wherein the molar ratio of clopidogrel to cyclodextrin in the mixed solution is 1 (1-20).

10. The method for preparing clopidogrel inclusion co-crystal according to any one of claims 6 to 9, wherein the process of adding clopidogrel Lei Rongye satisfies one or more of the following conditions:

(1) The adding time is controlled to be 0.5 to 30 minutes according to 1 to 3mL of clopidogrel Lei Rongye;

(2) The aqueous cyclodextrin solution is stirred at a speed of 50rpm to 1000rpm.

11. An antiplatelet pharmaceutical composition comprising clopidogrel inclusion co-crystal of any one of claims 1 to 5 and a carrier or excipient.

12. Use of clopidogrel inclusion co-crystal as defined in any one of claims 1 to 5 in the preparation of a chemical formulation, a medicament or a food.