KR20130033242A - Clopidogrel co-crysral - Google Patents

Abstract

PURPOSE: A clopidogrel co-crystal containing clopidogrel bisulfate and nicotinamide is provided to enhance stability to heat, light, or moisture, and to ensure solubility in water. CONSTITUTION: A clopidogrel co-crystal contains clopidogrel bisulfate, and nicotinamide or isonicotinamide. A method for preparing the clopidogrel co-crystal comprises: a step of dissolving clopidogrel bisulfate, and nicotinamide or isonicotinamide in an organic solvent for preparing a mixture solution; a step of generating the clopidogrel co-crystal; and a step of collecting the clopidogrel co-crystal.

Description

Clopidogrel co-crysral

The present invention provides a co-crystal of clopidogrel consisting of clopidogrel hydrogensulfate and nicotinamide or clopidogrel hydrogen sulfate and isonicotinamide, a pharmaceutical composition comprising the co-crystal of clopidogrel as an active ingredient, and co-crystal of clopidogrel as described above. It relates to a manufacturing method of.

Clopidogrel hydrogensulfate is represented by the formula (1) and is marketed as (S)-(+)-clopidogrel bisulfate on the market.

[Formula 1]

Clopidogrel hydrogen sulfate has the activity of inhibiting platelet aggregation induced by adenosinediphosphate (ADP), collagen (collagen) and thrombin. Therefore, it is marketed as a substance useful for the treatment and prevention of platelet aggregation-related diseases, such as stroke, cerebral atherosclerosis, myocardial infarction, angina pectoris, arrhythmia, peripheral arterial obstruction and Burger's disease, and is used in the market for chronic atherosclerotic cardiovascular disease. And it has been found that there is a reducing effect of the disease that can occur in a person suffering from cerebrovascular disease.

U.S. Patent No. 4,529,596 discloses an application to the treatment of clopidogrel as a platelet aggregation inhibitor and an antithrombotic agent and a method for its preparation. U.S. Patent No. 4,847,265 describes a method for preparing hydrogen sulfate of clopidogrel. US Pat. Nos. 6,504,040 and 6,429,210 disclose homologues of clopidogrel hydrogen sulfate.

Clopidogrel free base is an oily substance that is difficult to purify, and it is difficult to maintain the purity required for pharmaceuticals. Therefore, clopidogrel is converted into an easy-to-purify and stable crystalline substance for use as an active ingredient in pharmaceutical compositions. Use it. Crystalline clopidogrel that is commonly used is prepared to form acid addition salts. Flavix ™ (PLAVIXR, Sanofi-Sintravosa), currently commercially available as clopidogrel drug, is clopidogrel hydrogensulfate (European Patent 281,459 B1, U.S. Patent 4,847,265 and U.S. Patent 6,429,210).

The substance used as an active ingredient in a pharmaceutical composition applied for medicinal purposes shows sufficient therapeutic efficacy in clinical practice, and there are several considerations to reduce side effects. The first must be high enough, the second must be sufficiently stable against heat and moisture, and the third must have sufficient solubility in water. Since the acid addition salts of clopidogrel or polycrystalline polymorphs thereof developed so far are not sufficient in terms of stability, the development of pharmaceutical compositions using the acid addition salts of clopidogrel or polycrystalline polymorphs having improved stability in the field still need to be solved. One of the challenges.

In U.S. Patent No. 4,848,265, the preferred type I enantiomer of clopidogrel has excellent anticoagulant platelet action, whereas the corresponding type I type levitotatory enantiomer is weaker and less active among the two isomers. Disclosed. U.S. Patent No. 4,848,265 also discloses various other salts of compounds of type I, such as hydrochloride, carboxylic acid and sulfonic acid salts, such as acetic acid, benzoic acid, fumaric acid, maleic acid, citric acid, tartaric acid, gentisic acid, methanesulfonic acid, ethanesulfonic acid, Salts of benzenesulfonic acid and lauryl sulfonic acid are disclosed. According to U.S. Patent No. 4,848,265, these salts are generally precipitated in amorphous form and hygroscopic, making it difficult to handle on an industrial scale.

In addition, Korean Patent Publication Nos. 10-2005-0008692 and 10-2004-0101503 obtain clopidogrel benzenesulfonate as a solvate form with toluene or dioxane. It is not appropriate because it does not comply with International Publication No. 10-2007-0125548.

Therefore, there is an urgent need to develop a new drug having improved heat and moisture stability and water solubility so that clopidogrel shows sufficient therapeutic effect and reduces side effects as a therapeutic agent for platelet aggregation-related diseases.

It is an object of the present invention to provide novel cocrystals of Clepidogrel.

Another object of the present invention is to provide a pharmaceutical composition comprising the cocrystal of Clepidogrel as an active ingredient.

Still another object of the present invention is to provide a method for preparing copicrystal of clepidogrel.

In order to solve the above problems, the present invention is characterized by the cocrystal of clopidogrel consisting of clopidogrel hydrogen sulfate and nicotinamide, or clopidogrel hydrogen sulfate and isnicotinamide.

In addition, the present invention is characterized by a pharmaceutical composition containing the above-mentioned co-crystal of clopidogrel as an active ingredient.

The present invention also provides a process for preparing a mixed solution by dissolving clopidogrel hydrogen sulfate and nicotinamide or isonicotinamide in an organic solvent; Producing a cocrystal of clopidogrel consisting of clopidogrel hydrogen sulfate and nicotinamide or isnicotinamide; And recovering the cocrystal of the produced clopidogrel; Characterized by a method for producing a co-crystal of clopidogrel comprising a.

The cocrystal of clopidogrel according to the present invention is simple and easy to manufacture and commercial mass production is possible.

The cocrystal of clopidogrel according to the present invention satisfies the physical properties required as an active ingredient of a pharmaceutical composition such as excellent stability against heat, light or moisture, and excellent solubility in water.

The cocrystal of clopidogrel according to the present invention is useful as a therapeutic agent for diseases treatable by conventional clopidogrel drugs, such as anticoagulants, angina pectoris, antiplatelet agents, thrombolytic agents, or atherosclerosis agents.

1 is a powder XRD pattern for cocrystals of clopidogrel hydrogen sulfate and nicotinamide.
Figure 2 is a powder XRD pattern for cocrystals of clopidogrel hydrogen sulfate and isnicotinamide.
Figure 3 is a DSC thermal analysis of the cocrystal of clopidogrel hydrogen sulfate and nicotinamide.
4 is a DSC thermal analysis diagram for cocrystal of clopidogrel hydrogen sulfate and isnicotinamide.
5 is an FTIR spectrum of cocrystal of clopidogrel hydrogen sulfate and nicotinamide.
6 is an FTIR spectrum of the cocrystal of clopidogrel hydrogen sulfate and isnicotinamide.
7 is a powder XRD pattern for Clopidogrel hydrogen sulfate crystal Form 1;
8 is a powder XRD pattern for Clopidogrel Hydrogen Sulfate Crystal Form 2.
9 is a DSC thermogram for Clopidogrel Hydrogen Sulfate Crystal Form 2.
10 is an FTIR spectrum of Clopidogrel Hydrogen Sulfate Crystal Form 2.
FIG. 11 is a graph comparing the solubility of clopidogrel hydrogen sulfate crystal type 2 and co-crystal of clopidogrel hydrogen sulfate and nicotinamide. FIG.

The present invention relates to a co-crystal of clopidogrel consisting of clopidogrel hydrogen sulfate and nicotinamide, or consisting of clopidogrel hydrogen sulfate and isnicotinamide.

Powder XRD patterns, infrared spectroscopy (FTIR) spectra, and DSC thermal analyzes for the cocrystal of clopidogrel according to the present invention are shown in FIGS. 1 to 6. According to the analysis results of FIGS. 1 to 6, it can be seen that the cocrystal of clopidogrel according to the present invention shows no tendency with clopidogrel hydrogen sulfate.

The cocrystals of clopidogrel hydrogen sulfate and nicotinamide showed diffraction angles of 8.3, 15.0, 7.7, 18.5, 18.8, 19.8, 20.3, 20.6, 21.7, 22.6, 23.0, 23.6, 25.0, 25.2, 26.1, and 27.4 in the powder XRD pattern. , I / I ₀ > 10%). The cocrystals of clopidogrel hydrogen sulfate and isonicotinamide showed diffraction angles of 7.5, 11.8, 17.2, 17.6, 17.8, 18.9, 19.5, 21.0, 22.1, 22.3, 22.8, 23.3, 23.7, and 24.6 in powder XRD patterns. I / I ₀ > 10%).

In addition, the maximum endothermic peak was observed at 158.17 ° C on the spectra analyzed by differential scanning calorimetry (DSC) for cocrystal of clopidogrel hydrogen sulfate and nicotinamide. The maximum endothermic peak was observed at 189.19 ° C on the spectra of clopidogrel hydrogen sulfate and isonicotinamide, which were analyzed by differential scanning calorimetry (DSC).

For reference, the powder XRD patterns for Clopidogrel Hydrogen Sulfate Crystal Form 1 and Crystal Form 2 were attached to FIGS. 7 and 8, respectively. DSC thermograms and FTIR spectra of Clopidogrel Hydrogen Sulfate Crystal Form 2 were attached to FIGS. 9 and 10, respectively. According to the above analysis results, it can be confirmed that the cocrystal of clopidogrel of the present invention is a novel substance having physicochemical properties completely different from the existing clopidogrel hydrogen sulfate crystal form.

In addition, the co-crystal of clopidogrel according to the present invention was excellent in stability to light and heat or moisture, it was confirmed through a comparative experiment that the excellent dissolution properties in water. [See Experimental Examples 1 to 3]

As described above, the co-crystal of clopidogrel according to the present invention satisfies all the requirements as an active ingredient of the pharmaceutical composition, that is, the chemical purity of the crystal, the stability to heat and light or moisture, and the solubility in water. Accordingly, the present invention provides a pharmaceutical composition containing the above-mentioned cocrystal of clopidogrel as an active ingredient.

In the pharmaceutical composition according to the present invention, the cocrystal of clopidogrel as an active ingredient may be included in the range of 0.1 to 99% by weight based on the total weight of the pharmaceutical composition.

The daily effective dosage of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day based on an adult, but the dosage may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Alternatively, the pharmacist may decide to divide and administer once or several times a day at regular intervals.

The pharmaceutical composition of the present invention can be administered orally or parenterally by formulating in a conventional formulation method, including a carrier, adjuvant, or diluent, which is commonly used as an excipient, together with cocrystal of clopidogrel as an active ingredient, and general pharmaceuticals. It can be used in the form of a formulation.

Excipients that can be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like. Substituted and substituted as diluents such as powdered cellulose, microcrystalline cellulose, ultrafine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salt and others Cellulose derived materials such as cellulose which is not present; Starch; Pregelatinized starch; Inorganic diluents such as calcium carbonate and calcium diphosphate, and other diluents commonly known in the pharmaceutical formulation art. Other suitable diluents also include waxes, sugars and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrins and gelatin. The present invention may be used as additional excipients such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes, including sodium starch glycolate, crospovidone, Low substituted hydroxypropyl cellulose and others can be used. Also excipients include tableting glidants such as magnesium and calcium stearate and sodium stearyl fumarate; Condiment; sweetener; antiseptic; Glidants such as pharmaceutically acceptable dyes and silicon dioxide can be used.

The route of administration of the pharmaceutical composition may vary depending on the nature and severity of the condition to be treated. In the case of oral administration, solid preparations such as tablets, powders, granules, aggregates, capsules, suppositories, sachets, troches, lozenges, etc., as well as solutions, syrups, suspensions, and exciters It can be prepared as. Of course, the capsule agent may comprise a solid composition in a capsule or other conventional encapsulating material that can be made from gelatin. Tablets and powders may be coated. Tablets and powders can also be coated with enteric coatings. The enteric coated powder forms phthalic cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, copolymers of styrene and maleic acid, copolymers of methacrylic acid and methyl methacrylate, and similar materials. It may have a coating comprising, and if desired they may be used with suitable plasticizers and / or extenders. Coated tablets may have a coating on the surface of the tablet or may be tablets comprising powders or granules with an enteric coating. Formulations for parenteral administration include non-aqueous solvents, suspensions, emulsions, lyophilized preparations and sterile aqueous solutions.

On the other hand, the cocrystal of clopidogrel according to the present invention can be easily prepared by a solvent evaporation method, a cooling method, or a solvent crystallization method using a nonsolvent as a crystallization solvent.

Hereinafter, a method for preparing cocrystal of clopidogrel according to the present invention will be described in detail.

The first step is to prepare a mixed solution by dissolving clopidogrel hydrogen sulfate and nicotinamide or isonicotinamide in an organic solvent.

The organic solvent used in the first step is a good solvent for dissolving clopidogrel hydrogen sulfate and nicotinamide or isonicotinamide, and methanol, ethanol, 1-propanol, acetic acid, acetone, formic acid, N-methyl-2-pyrrolidone (NMP), acetonitrile, N, N-dimethylsulfoxide (DMSO) or two or more mixed solvents selected therefrom can be used. The amount of the organic solvent used may vary depending on the selected solvent or dissolution temperature, and may be appropriately adjusted within a range capable of maintaining the concentration of clopidogrel at 0.001 to 10 g / mL.

In order to prepare the mixed solution, there is no particular limitation in the present invention with respect to the order of adding clopidogrel hydrogen sulfate and co-crystal forming material to the organic solvent. Sufficient stirring dissolves clopidogrel hydrogen sulfate and nicotinamide or isonicotinamide. If necessary, the mixed solution is warmed to complete dissolution. At this time, the dissolution temperature is a reflux temperature range of 0 ° C to a solvent, preferably 20 ° C to 150 ° C temperature range, if necessary can be obtained by heating in a temperature range of 30 ° C to 150 ° C completely dissolved transparent solution.

The second process is a process of producing cocrystals of clopidogrel hydrogen sulfate and nicotinamide or cocrystals of clopidogrel hydrogen sulfate and isnicotinamide.

Crystals may be produced by the 'solvent evaporation method' which evaporates the solvent while slowly stirring the mixed solution. Solvent evaporation is to maintain a temperature range of 10 ℃ to 150 ℃, preferably 20 ℃ to 70 ℃, if the evaporation temperature is maintained too high clopidogrel hydrogen sulfate decomposes can be a factor that reduces the yield of co-crystals It is better to keep below the decomposition temperature. The evaporation time of the solvent is 20 minutes to 70 hours, and if it is too fast, the purity of the co-crystal may be lowered.

Alternatively, crystals may be generated by a 'cooling method' in which the mixed solution is rapidly or slowly cooled to a temperature of -30 ° C to 20 ° C to induce a supersaturated state. Cooling rate is preferably maintained at 0.01 to 20 ℃ / min, low cooling rate, the long crystallization time is long, the productivity can be low, high cooling rate, small particle size co-crystals are formed to recover the crystals It can be difficult.

Alternatively, crystals may be produced by the 'solvent crystallization method' in which a nonsolvent is further added to the mixed solution as a crystallization solvent. The crystallization solvent used at this time may be a non-solvent having low solubility in clopidogrel hydrogen sulfate, for example, isopropanol, butanol, cyclohexane, pentanol, chloroform, or a mixture of two or more selected from them.

In addition, crystal seeds may be added to the mixed solution to promote the formation of co-crystals.

The third process is a process of recovering the cocrystal of the clopidogrel produced.

As a method for recovering the co-crystal, a conventional method is appropriately used, for example, the co-crystal is recovered from the reaction mixture by gravity or suction filtration, centrifugal separation, or a similar method. The recovered co-crystals may be washed with the non-solvent described above to further increase the purity of the co-crystals.

The present invention as described above will be described in more detail based on the following examples. However, this is only to help the understanding of the configuration and operation of the present invention, the scope of the present invention is not limited by the following examples.

[Example]

Example 1 Preparation of Cocrystal of Clopidogrel Hydrogen Sulfate and Nicotinamide by Solvent Evaporation

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Nicotinamide (2.1 g) was also dissolved in propanol (60 mL) and then added to the solution and stirred for 10 minutes. After stirring, the mixture was slowly stirred at 25 ° C and evaporated. Within a short time, crystalline forms of clopidogrel hydrogen sulfate and nicotinamide cocrystal spontaneously formed. When all of the solvent in the solution was evaporated to dry in a drier at 50 ℃ for one day to recover only crystals to obtain 8.5 g (yield 93%, purity 99%).

Powder XRD spectrum (Fourier transform infrared (FT-IR)) spectrum, and differential scanning calorimetry for the cocrystal of clopidogrel hydrogen sulfate and nicotinamide prepared in Example 1 (Differential Scanning Calorimeter Thermogram) was attached to FIGS. 1, 3, and 5, respectively.

Example 2. Cocrystal Preparation of Clopidogrel Hydrogen Sulfate and Isonicotinamide by Solvent Evaporation

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Also isicotinamide (2.1 g) was dissolved in propanol (60 mL) and added to the solution and stirred for 10 minutes. After stirring, the mixture was slowly stirred at 25 ° C and evaporated. Within a short time, crystalline forms of clopidogrel hydrogen sulfate and isicotinamide cocrystal spontaneously formed. When all of the solvent in the solution was evaporated to dry in a 50 ℃ dryer for one day only to recover the crystals to obtain about 8.6 g (yield 94%, purity 99%).

Powder XRD spectrum (Fourier transform infrared (FT-IR)) spectrum, and differential scanning calorimetry for the cocrystal of clopidogrel hydrogen sulfate and isonicotinamide prepared in Example 2 Figures (Differential Scanning Calorimeter Thermogram) are attached to FIGS. 2, 4, and 6, respectively.

Example 3 Cocrystal Preparation of Clopidogrel Hydrogen Sulfate and Nicotinamide by Solvent Crystallization

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Nicotinamide (2.1 g) was also dissolved in propanol (60 mL) and then added to the solution and stirred for 10 minutes. After 20-24 hours of stirring, nonsolvent isopropanol (IPA, 50 mL) was added and stirred again. After 24 hours, it was confirmed that crystals were formed between the solutions, and then filtered through a filter to recover only the crystals and dried for a day to obtain about 8.1 g (yield 89%, 99% purity).

Example 4 Cocrystal Preparation of Clopidogrel Hydrogen Sulfate and Isonicotinamide by Solvent Crystallization

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Also isicotinamide (2.1 g) was dissolved in propanol (60 mL) and added to the solution and stirred for 10 minutes. After 20-24 hours of stirring, nonsolvent isopropanol (IPA, 50 mL) was added and stirred again. After 24 hours, it was confirmed that crystals were formed between the solutions, and then filtered through a filter to recover only the crystals and dried for a day to obtain about 8.2 g (yield 90%, 99% purity).

Example 5 Cocrystal Preparation of Clopidogrel Hydrogen Sulfate and Nicotinamide by Cooling Method

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Nicotinamide (2.1 g) was also dissolved in propanol (60 mL) and added to the solution and stirred for 10 minutes. After stirring, the mixture was slowly cooled to −25 ° C. and stirred again for 3 hours after crystals were formed in the solution. The resulting solution was filtered through a filter to recover only crystals and dried for one day to obtain about 8 g (88% yield, 99% purity) of the co-crystals.

Example 6 Cocrystal Preparation of Clopidogrel Hydrogen Sulfate and Isonicotinamide by Cooling Method

Clopidogrel hydrogen sulfate (7 g) was dissolved in 60 ° C propanol (180 mL) while warming. Also isicotinamide (2.1 g) was dissolved in propanol (60 mL) and added to the solution and stirred for 10 minutes. After stirring, the mixture was slowly cooled to −25 ° C. and stirred again for 3 hours after crystals formed in the solution. The resulting solution was filtered through a filter to recover only the crystals and dried for one day to obtain 7.9 g (yield 87%, 99% purity) of the co-crystals.

Experimental Example

Experimental Example 1 Stability of Clopidogrel's Co-Crystal to Heat and Light

In order to confirm the stability of heat and light to the co-crystal of clopidogrel of the present invention, the following experimental method was performed to compare the stability of clopidogrel hydrogen sulfate and heat and light.

 <Experimental Method>

After standing at room temperature under ultraviolet light (313 nm or less) for 80 hours, the residual amount was measured by high performance liquid chromatography (HPLC), and the results are shown in Table 1 below.

division Survival rate (%) Clopidogrel Hydrogen Sulfate Crystal Form 2 ^* 95.8 Cocrystal of Clopidogrel Hydrogen Sulfate and Nicotinamide 97.2 Cocrystallization of Clopidogrel Hydrogen Sulfate and Isnicotinamide 98.1 * Compound disclosed in Korean Patent Laid-Open No. 10-2006-0018554

According to Table 2, the clopidogrel co-crystal of the present invention is characterized in that it is very stable to heat and light as compared to the conventional clopidogrel hydrogen sulfate crystal type 2, so it is useful in the manufacture of pharmaceuticals.

Experimental Example 2. Moisture Stability of Cocrystal of Clopidogrel

Clopidogrel is generally known to readily hydrolyze under moisture conditions. The following experimental method was performed to compare the water stability of the cocrystal of clopidogrel and clopidogrel hydrogen sulfate of the present invention.

<Experimental Method>

In the light-blocked (30 ℃ / 60% relative humidity) condition and stored for 0 days and 1 month under the airtight container conditions, the residual ratio was measured by HPLC analysis, respectively, the results are shown in Table 2 below.

Residual rate (%), (condition: 30 ℃, relative humidity 60%) division first 1 month Clopidogrel Hydrogen Sulfate Crystal Form 2 ^* 100 99.1 Cocrystal of Clopidogrel Hydrogen Sulfate and Nicotinamide 100 99.6 Cocrystallization of Clopidogrel Hydrogen Sulfate and Isnicotinamide 100 99.7 * Compound disclosed in Korean Patent Laid-Open No. 10-2005-0077490

According to Table 2, the clopidogrel co-crystal of the present invention is characterized in that the chemical stability is very excellent even in the moisture conditions compared to the conventional clopidogrel hydrogen sulfate crystal type 2, it is useful in the manufacture of pharmaceuticals.

Experimental Example 3. Solubility of Cocrystal of Clopidogrel

The solubility and dissolution rate of water in pharmaceuticals are closely related to bioavailability. The following experimental method was carried out to compare the solubility and dissolution rate of the coclocrystal of clopidogrel of the present invention and the existing Clopidogrel hydrogen sulfate crystal type 2.

<Experimental Method>

After dissolving each active ingredient in general distilled water (pH 5.6), the saturated solution was analyzed by high performance liquid chromatography, and the results are shown in Table 3 and FIG. 11.

division Solubility in water
(mg / mL, 25 ℃) Clopidogrel Hydrogen Sulfate Crystal Form 2 ^* 9.47 Cocrystal of Clopidogrel Hydrogen Sulfate and Nicotinamide 142 Cocrystallization of Clopidogrel Hydrogen Sulfate and Isnicotinamide 143 * Compound disclosed in Korean Patent Laid-Open No. 10-2005-0077490

According to the results of Table 3, it can be confirmed that the cocrystal of clopidogrel of the present invention is superior in solubility by about 15 times as compared to existing clopidogrel hydrogen sulfate crystal type 2.

11 shows the results of measuring the solubility of the clopidogrel hydrogen sulfate crystal type 2, the copi crystal of clopidogrel hydrogen sulfate, and nicotinamide while changing the water temperature in a graph. Referring to FIG. 11, the co-crystal of clopidogrel hydrogen sulfate and nicotinamide has a sufficiently high solubility at room temperature of 25 ° C., and the solubility of the clopidogrel hydrogen sulfate and nicotinamide is rapidly increased as the temperature of water increases.

As confirmed from the results of Experimental Examples 1 to 3, the co-crystal of clopidogrel of the present invention satisfies all the requirements for the active ingredient of the pharmaceutical composition as a novel substance.

Therefore, it can be seen that the cocrystal of clopidogrel of the present invention is useful as an active ingredient of a pharmaceutical composition in which clopidogrel hydrogen sulfate is included as an active ingredient.

Claims (13)

A cocrystal of clopidogrel, comprising clopidogrel hydrogen sulfate and nicotinamide.
The method of claim 1,
Clopidogrel cocrystal, characterized in that the diffraction angle (2θ) on the powder XRD spectrum is 8.3, 15.0, 7.7, 18.5, 18.8, 19.8, 20.3, 20.6, 21.7, 22.6, 23.0, 23.6, 25.0, 25.2, 26.1, 27.4 .
The method of claim 1,
A cocrystal of clopidogrel, characterized in that the maximum endothermic peak in the spectrum analyzed by differential scanning calorimetry (DSC) is observed at 158.17 ° C.
A cocrystal of clopidogrel, comprising clopidogrel hydrogen sulfate and isnicotinamide.
The method of claim 4, wherein
The cocrystal of clopidogrel, characterized in that the diffraction angle (2θ) on the powder XRD spectrum is 7.5, 11.8, 17.2, 17.6, 17.8, 18.9, 19.5, 21.0, 22.1, 22.3, 22.8, 23.3, 23.7, 24.6.
The method of claim 4, wherein
A cocrystal of clopidogrel, characterized in that the maximum endothermic peak in the spectrum analyzed by differential scanning calorimetry (DSC) is observed at 189.19 ° C.
A pharmaceutical composition useful as an anticoagulant, angina treatment agent, antiplatelet agent, thrombolytic agent, or atherosclerosis agent, characterized in that the cocrystal of clopidogrel of any one of claims 1 to 6 is included as an active ingredient.
Preparing a mixed solution by dissolving clopidogrel hydrogen sulfate and nicotinamide or isonicotinamide in an organic solvent;
Producing a cocrystal of clopidogrel consisting of clopidogrel hydrogen sulfate and nicotinamide or isnicotinamide; And
Recovering the cocrystal of the produced clopidogrel;
Method for producing a co-crystal of clopidogrel comprising a.
The method of claim 8,
Method for producing a co-crystal of clopidogrel, characterized in that for heating to a temperature of 30 ℃ to 150 ℃ for dissolution.
The method of claim 8,
A method for producing copicrystal of clopidogrel, characterized in that a crystallization solvent is added to produce the cocrystal.
The method of claim 8,
Method of producing a co-crystal of clopidogrel, characterized in that to induce supersaturation by cooling to -30 ℃ to 20 ℃ temperature to produce the co-crystal.
The method of claim 8,
The organic solvent is ethanol, methanol, 1-propanol, acetic acid, acetone, formic acid, N-methyl-2-pyrrolidone (NMP), acetonitrile, dimethyl sulfoxide (DMSO) or a mixture of two or more such organic solvents. A process for producing copicrystal of clopidogrel, characterized in that one solvent is used.
The method of claim 8,
The crystallization solvent is isopropyl alcohol (IPA), butanol, cyclohexane, pentanol, chloroform, or a method for producing a co-crystal of clopidogrel, characterized in that using two or more mixed solvents selected from them.

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