KR20090060670A - Crystalline sulfonic acid salt of ziprasidone, a process for the preparation thereof, and a pharmaceutical composition comprising the same - Google Patents

Abstract

A ziprasidone besylate of crystalline is provided to ensure excellent stability, solubility, non-hydroscopicity and higher elution rate than ziprasidone hydrochloride. A method for manufacturing a ziprasidone besylate of crystalline comprises: a step of reacting ziprasidone and benzenesulfonic acid in inert solvent; and a cooling the mixture to -10~10°C. The inert solvent is acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, isopropyl ether, methyl ethyl ketone, dichloromethane, tetrahydrofuran or their mixture. A composition for treating schizophrenia or bipolar disorder-related mania comprises ziprasidone besylate and pharmaceutically allowable carrier.

Description

Crystalline ziprasidone sulfonate, a method for preparing the same, and a pharmaceutical composition comprising the same {Crystalline sulfonic acid salt of ziprasidone, a process for the preparation according to, and a pharmaceutical composition comprising the same}

The present invention relates to ziprasidone (5- (2- (4- (1,2-benzisothiazol-3-yl-1-piperazinyl) -ethyl) -6-chloro-1,3 The present invention relates to a novel crystalline sulfonate of -dihydro-2- (1H) -indol-2-one), a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.

Ziprasidone is an atypical antipsychotic drug with multiple antagonisms on the 5-HT ₂ / D ₂ receptor. It is produced and sold under the trade name GEDOON.

Ziprasidone bases and preparation methods thereof, and Ziprasidone hydrochloride hemihydrate are described in US Pat. No. 4,831,031. In addition, U.S. Patent No. 5,312,925 discloses ziprasidone hydrochloride monohydrate, and according to the patent document, the hygroscopicity that changes into monohydrate form over time even when manufactured in the form of anhydride or hemihydrate due to the properties of ziprasidone hydrochloride. Have Thus, since ziprasidone hydrochloride monohydrate is substantially stable in terms of hygroscopicity, problems due to weight change of the pharmaceutically active ingredient can be alleviated during the final formulation.

Geldox, a formulation of ziprasidone on the market, contains ziprasidone hydrochloride monohydrate and is sold in 20, 40, 60, and 80 mg units. Injectable geldox contains ziprasidone mesylate trihydrate in lyophilized form and contains an equivalent of 20 mg of ziprasidone base. The ziprasidone mesylate trihydrate is described in US Pat. Nos. 6,110,918 and 5,245,765 with monohydrate. However, ziprasidone hydrochloride monohydrate commercially available for oral use is stable in terms of hygroscopicity but has a low solubility problem.

In general, in order to prepare salts of pharmaceutical compositionally good properties, physicochemical criteria such as (1) good solubility, (2) good stability, (3) non-hygroscopicity, and (4) processability into tablet formulations must be met.

For this reason, many patents have been applied through research through polymorphism and particle size control to develop high quality ziprasidone hydrochloride. International Patent Publication WO 05/035531 is to obtain a compound excellent in terms of pharmaceutical properties, such as fluidity and solubility of ziprasidone hydrochloride, various polymorphs of ziprasidone hydrochloride (E, F, G, I, J, E1 And amorphous forms are disclosed.

However, ziprasidone hydrochloride becomes a problem in that it becomes hygroscopic even when it is made into anhydride form or amorphous form to improve its physical properties and becomes monohydrate crystalline form. In addition, ziprasidone hydrochloride monohydrate is stable in terms of hygroscopicity, but has a problem of low solubility. Therefore, there is still a need to develop ziprasidone in a form having pharmaceutical properties.

Accordingly, the present inventors earnestly researched to make ziprasidone have better physical properties, and when ziprasidone is combined with sulfonic acid other than hydrochloric acid to form crystalline ziprasidone sulfonate, it is superior to ziprasidone hydrochloride. The invention has been found to have stability, solubility, non-hygroscopicity, and dissolution rate to complete the present invention.

Accordingly, it is an object of the present invention to provide ziprasidone sulfonate of crystalline form which is excellent in terms of stability, solubility, non-hygroscopicity, and dissolution rate.

Another object of the present invention is to provide a method for preparing the crystalline ziprasidone sulfonate.

Still another object of the present invention is to provide a pharmaceutical composition containing the crystalline ziprasidone sulfonate as an active ingredient.

In order to achieve the above object, the present invention provides a crystalline ziprasidone besylate.

The ziprasidone besylate of the crystalline form

Reacting ziprasidone and benzenesulfonic acid in an inert solvent; And

Cooling the reaction mixture to -10 ~ 10 ℃ can be prepared by a method comprising the step of forming a crystalline form.

The present invention also provides a composition for treating schizophrenia or bipolar disorder-related mania comprising the crystalline ziprasidone besylate and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a salt form of a new crystalline form of ziprasidone having superior stability, solubility, and non-hygroscopicity compared to conventional ziprasidone hydrochloride and having a higher dissolution rate than ziprasidone hydrochloride when formulated, the present invention Provides crystalline ziprasidone besylate.

The ziprasidone besylate of the crystalline form of the present invention is preferably a crystalline ziprasidone besylate having a peak at a diffraction angle of at least 17.36, 20.66, 22.99, and 24.09 at 2θ when measured by X-ray powder diffraction. . In addition, the crystalline ziprasidone besylate more preferably has the X-ray powder diffraction pattern of FIG.

The ziprasidone besylate of the crystalline form according to the present invention is in the form of an anhydride that is stable to moisture, and unlike the conventional anhydride of ziprasidone hydrochloride, changes to monohydrate over time, in the form of a hydrate over time. Does not change. Accordingly, crystalline ziprasidone besylate is excellent in terms of hygroscopicity affecting formulation processability and stability.

In addition, the crystalline ziprasidone besylate has superior stability in comparison with ziprasidone hydrochloride monohydrate in terms of stability. After four weeks of storage in a chamber at 60 ° C and 80% RH, accelerated stability tests were performed to determine the change in content and the degree of change of the soft substance. After 4 weeks, there was little change in the content and formation of the soft substance. Better results were obtained compared to sidon hydrochloride monohydrate.

In addition, the crystalline ziprasidone besylate has superior solubility compared to ziprasidone hydrochloride monohydrate. As a result of measuring solubility under distilled water, pH 1.2, 4.0, and 6.8, respectively, it was confirmed that the crystalline ziprasidone besylate had higher solubility than ziprasidone hydrochloride monohydrate.

In addition to the hygroscopicity, storage stability, and solubility, the comparative dissolution test in terms of dissolution rate showed that the capsules prepared with ziprasidone besylate of the crystalline form of the present invention had a higher dissolution rate than currently available geldox (Pfizer). Appeared.

Thus, the crystalline ziprasidone besylate of the present invention has superior stability, solubility, and non-hygroscopicity compared to ziprasidone hydrochloride, has a higher dissolution rate than ziprasidone hydrochloride when formulated, and has excellent physical properties in terms of formulation. It can be said to have.

The present invention also provides

Reacting ziprasidone and benzenesulfonic acid in an inert solvent; And

It provides a method for producing a crystalline ziprasidone besylate comprising the step of cooling the reaction mixture to -10 ~ 10 ℃ to form a crystal form. This preparation method is represented by the following reaction scheme:

The benzenesulfonic acid used as a reactant has a LD ₅₀ (rat, oral administration) of 1,157 mg / kg in the literature, and is used for the preparation of salts of a number of medicines, such as amlodipine, fenbutamide, and atracurium. Ziprasidone besylate according to the present invention can be said to be in the form of a pharmaceutically acceptable safe salt.

According to the embodiment of the present invention more specifically,

Adding ziprasidone in an inert solvent to prepare a ziprasidone solution;

Dropping and stirring benzenesulfonic acid diluted in an inert solvent while refluxing the ziprasidone solution;

Stirring the reaction mixture at -5 ° C to reflux temperature;

Then, cooling and stirring the reaction mixture to -10 ~ 30 ℃ to form a crystalline form; And

Filtering the crystals and washing with an inert solvent.

In the preparation method, 1-5 equivalents of benzenesulfonic acid may be reacted with respect to 1 equivalent of ziprasidone, and preferably 1.2-1.7 equivalents of benzenesulfonic acid may be reacted. The concentration of benzenesulfonic acid in the diluted inert solvent may be 1 to 5 mol / L.

In the step of dropwise addition and stirring benzenesulfonic acid diluted in an inert solvent while refluxing the ziprasidone solution, the dropping may be performed for 30 minutes to 2 hours, the stirring may be carried out for 1 to 5 hours. In the step of dropwise adding and stirring the benzenesulfonic acid diluent while refluxing the ziprasidone solution to the preparation method, the first stirring under reflux conditions is to quantitatively bind benzenesulfonic acid to ziprasidone. Then, the step of stirring the reaction mixture at -5 ℃ ~ reflux temperature may be performed, and then the step of stirring the reaction mixture at -10 ~ 30 ℃ for 1 to 5 hours. The stirring step may be preferably performed at -10 ~ 10 ℃. In the above production method, the total reaction time of dropwise addition and stirring the benzenesulfonic acid diluent to the ziprasidone solution may be 2 to 15 hours, preferably 7 to 8 hours.

Acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, isopropyl ether, methylethylketone, dichloromethane, tetrahydrofuran, or a combination thereof may be used as the inert solvent usable in the preparation method of the present invention. However, the present invention is not limited thereto, and preferably ethanol may be used.

According to the production method of the present invention as described above, crystalline ziprasidone besylate can be produced in high yield of 97.0% or more and high purity of 99.0% or more.

The present invention also provides a composition for treating schizophrenia or bipolar disorder mania comprising a crystalline ziprasidone besylate and a pharmaceutically acceptable carrier.

The composition of the present invention can be formulated into parenteral formulations, such as oral or injection preparations such as granules, powders, solutions, tablets, capsules, or dry syrups, but is not limited to such formulations. Preferably the compositions of the present invention may be in the form of tablets or capsules or in the form of solutions or injections.

The therapeutically effective amount of the crystalline ziprasidone besylate used in the compositions of the present invention may range from 10 to 200 mg per day as ziprasidone base, and the unit dosage form may range from 10 to 80 mg. May contain ziprasidone besylate.

As the pharmaceutically acceptable carrier used in the composition of the present invention, one or two or more of conventional excipients, disintegrants, binders, lubricants and the like may be selectively used. For example, when the composition of the present invention is prepared in a solid form such as tablets or hard capsules, microcrystalline cellulose, lactose, low-substituted hydroxycellulose and the like can be used as excipients, sodium starch glycolate, anhydrous as a disintegrant. Calcium monohydrogen phosphate may be used. As the binder, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like can be used. The lubricant can be selected from magnesium stearate, silicon dioxide, talc and the like.

In addition, additives that provide gloss to tablets, such as anhydrous dibasic calcium phosphate, may be used and may be coated with a water insoluble material to prevent moisture in the air from penetrating into the tablet. At this time, the coating base should have a dense molecular structure and is not easily dissolved in an aqueous solution. As such coating agents, polymer materials such as methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and polyvinyl alcohol can be used. These polymeric materials may be used alone or in combination for coating. In addition, the coating may include additives, such as plasticizers, preservatives, colorants, light-shielding agents, etc. that can be added to the coating base conventionally in the art.

The compositions of the present invention may be in the form of solutions and injections, such as sterile aqueous solutions, and may contain 10-40% propylene glycol, if necessary, and an amount of sodium chloride sufficient to prevent hemolysis (eg, about 1%). .

As mentioned above, the ziprasidone besylate of the crystalline form according to the present invention has excellent stability, solubility, and nonhygroscopicity compared to ziprasidone hydrochloride, and has a higher dissolution rate than ziprasidone hydrochloride when formulated, It has excellent physical properties.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example

After preparing the crystalline ziprasidone besylate through the production method of the present invention, physical properties such as hygroscopicity, acceleration stability, and solubility were measured. In addition, in order to determine the dissolution propensity according to the formulation of crystalline ziprasidone besylate, a capsule of crystalline ziprasidone besylate was prepared and compared with ziprasidone hydrochloride (Geldox) which is currently commercially available.

Example  1: crystalline form Ziprasidone Besylate  Produce

Ziprasidone (40 g, 96.8 mmol) was added to 400 mL of ethanol and refluxed for 1 hour. While refluxing 20.7 mg (145.2 mmol, 90%) of benzenesulfonic acid was diluted with 40 mL of ethanol and added dropwise for 1 hour. The reaction mixture was stirred at reflux for 2 hours, then cooled to 25 ° C. and stirred for 1 hour. Then, stirred at 4 ° C. for 4 hours. The resulting solid was filtered under reduced pressure and washed with 30 mL of ethanol. After vacuum drying at 60 ° C. for 24 hours, 53.6 g (yield: 97%) of the title compound were obtained.

As a result of ¹ H-NMR analysis of the product, the following data was obtained.

¹ H-NMR (δ, DMSO-d6): 9.75 (1H, br, s), 8.15 (2H, m), 7.60 (3H, m), 7.48 (1H, m), 7.30 (1H, m), 6.87 (1H, s), 4.15 (2H, d), 3.60 (2H, d), 3.50 (2H, s), 3.37 (6H, m), 3.10 (2H, m)

In addition, X-ray powder diffraction of the product was carried out. As a result, an X-ray powder diffraction pattern as shown in Fig. 1 was obtained, and it was confirmed that it had a peak at diffraction angles of 2θ of 17.36, 20.66, 22.99, and 24.09.

Example  2: crystalline Ziprasidone Besylate  Manufacture of capsule

The components shown in Table 1 were mixed to prepare a crystalline ziprasidone besylate capsule.

Each of the above components were mixed and filled into hard capsules using a capsule filling machine (manufactured by Bosche).

Comparative example  One: Ziprasidone  Preparation of Hydrochloride Anhydride

The preparation of ziprasidone hydrochloride anhydride was prepared according to the anhydride preparation in US 5312925 (KR 10-0278321).

750 ml of distilled water, 250 ml of concentrated hydrochloric acid (37.3%) and 50 g of anhydrous ziprasidone were added to the reactor. The reaction mixture was heated to 60-65 ° C. for 24 hours. The slurry was filtered while maintaining a high temperature (about 55 ° C.) and washed twice with 200 mL of distilled water. Drying for 7 hours in air at 40 ~ 50 ℃ made the water content 3.9%. Further drying at 50 ° C. for 21.5 hours made the water content of the material 0.19% to obtain hydrochloric anhydride.

Comparative example  2: Ziprasidone  Hydrochloride Monohydrate  Produce

The preparation of ziprasidone hydrochloride monohydrate was prepared according to the anhydride preparation in US 5312925 (KR 10-0278321). 5.00 g of ziprasidone, 75 ml of distilled water and 5.0 ml of concentrated hydrochloric acid (37.5%) were added to the reactor. The reaction mixture was heated to 60-65 ° C. and maintained at this temperature for 3 hours. The heating bath was removed and the slurry cooled to room temperature. The product was collected by filtration on a sintered glass filter. The product cake was washed with a small amount of demineralized water and then air dried at 50 ° C. The moisture content after drying was 4.2%. Ziprasidone hydrochloride monohydrate was obtained in 96% yield (5.43%).

Test Example  1: water absorption test

The water absorption test was carried out in the zipracidone besylate of the crystalline form prepared in Example 1 and the ziprasidone hydrochloride anhydride prepared in Comparative Example 1 in a 95% relative humidity holding chamber. Each water content at the start of the moisture uptake test was measured and then measured at 4 hours, 24 hours, and 10 days. Water content measurement was performed according to the Karl Fischer method. Thermogravimetric analysis was also performed. The Karl Fischer method was measured according to the KEPCO general test method, TGA (Themogravimetric analysis) was measured to 25 ~ 200 ℃ as the anhydrous nitrogen gas flow rate 70 cc / min, the temperature increase rate 5 ℃ / min.

The analytical results are summarized in Table 2 below.

Experimental results showed that the crystalline ziprasidone besylate, which is anhydride, hardly absorbs moisture by comparing the degree of water absorption according to the Karl Fischer method and the weight loss of the crystal water portion in the TGA. However, hydrochloride anhydride gradually absorbed over time to absorb more than one monohydrate (moisture: 3.8%) of water.

Test Example 2: Accelerated Stability Test

The ziprasidone besylate of crystalline form prepared in Example 1 and the ziprasidone hydrochloride monohydrate prepared in Comparative Example 2 were subjected to an accelerated stability test at 60 ° C. The content of each substance and the content of the flexible substance were measured over time. The results are summarized in Tables 3 and 4 below.

HPLC analysis conditions were as follows:

Detector: ultraviolet absorbance (wavelength 229 nm)

Column: octadecyl silica gel C18 (4.6 mm x 150 mm, 5 μm)

Mobile phase: potassium dihydrogen phosphate solution, 0.05 mol / L pH 3.0: methanol = 3: 2

Flow rate: 1.5 ml / min

Column temperature bath: 40 ° C

Analysis time: 50 minutes

As shown in Table 3 and 4, the crystalline form of ziprasidone besylate according to the present invention did not change the content, the soft substance in the accelerated stability test at 60 ℃, compared to that of ziprasidone hydrochloride monohydrate The degree appeared to be smaller. Accordingly, it can be seen that the crystalline ziprasidone besylate has superior chemical stability than ziprasidone hydrochloride monohydrate.

Test Example 3: Solubility Test

The ziprasidone besylate prepared in Example 1 and the ziprasidone hydrochloride monohydrate prepared in Comparative Example 2 were dissolved at 37 ° C. under distilled water and various pH solution conditions (pH 1.2, pH 4.0, and pH 6.8). Measured.

Solvent preparation conditions were as follows.

pH 1.2: USP simulated gastric fluid (no enzyme added)

pH 4.0: acetate buffer

pH 6.8: USP simulated intestinal fluid

Solubility measurement results are summarized in Table 5 below. In Table 5, the solubility is the solubility (mg / mL) converted to ziprasidone base.

According to the results shown in Table 5, the crystalline form of ziprasidone besylate according to the present invention was found to have higher solubility at all pH conditions compared to ziprasidone hydrochloride monohydrate. Thus, the ziprasidone besylate of the crystalline form of the present invention is expected to have higher bioavailability compared to ziprasidone hydrochloride monohydrate.

Test Example  4: comparative dissolution rate test

A comparative dissolution test of the capsule of crystalline ziprasidone besylate prepared in Example 2 was carried out with geldox (ziprasidone hydrochloride monohydrate) which is currently commercially available. In the dissolution test, the eluate contained 41.4 g of sodium dihydrogen phosphate monohydrate and 41.4 g of sodium dodecyl sulfonate in 5.5 L of a solution containing 0.05 mol / L potassium dihydrogen phosphate and 2 w / v% of sodium dodecyl sulfonate and pH 6.8 in water. 120 g was added to dissolve it, 5 N sodium hydroxide solution was adjusted to pH 6.8, and water was added to 6 L.

The measurement conditions of the eluted ziprasidone were as follows.

-Detector: ultraviolet absorbance photometer (wavelength 315nm)

Column: octylsilyl silicakel (4 mm x 80 mm, 5 μm)

Mobile phase: 5N potassium hydroxide solution is added to 0.05 mol / L potassium dihydrogen phosphate solution to adjust the pH to 6.5, and the solution and acetonitrile are mixed in a ratio of 11: 9.

Flow rate: 1 mL / min

-Column temperature: 40 ° C

The results of the dissolution test measured by this method are summarized in Table 6 below.

As shown in Table 6, it can be seen that crystalline ziprasidone besylate has a higher dissolution rate than geldox.

1 is an X-ray diffraction pattern of crystalline ziprasidone besylate according to an embodiment of the present invention.

Claims (8)

Crystalline ziprasidone besylate. The crystalline ziprasidone besylate of claim 1, having a peak at a diffraction angle of at least 17.36, 20.66, 22.99, and 24.09 in a 2θ in an X-ray diffraction pattern. 2. The crystalline ziprasidone besylate of claim 1, having the X-ray diffraction pattern of FIG. Reacting ziprasidone and benzenesulfonic acid in an inert solvent; And Method for producing a crystalline ziprasidone besylate comprising the step of cooling the reaction mixture to -10 ~ 10 ℃. The method of claim 4, wherein Adding ziprasidone in an inert solvent to prepare a ziprasidone solution; Dropping and stirring benzenesulfonic acid diluted in an inert solvent while refluxing the ziprasidone solution; Stirring the reaction mixture at -5 ° C to reflux temperature; Then, cooling the reaction mixture to -10 ~ 10 ℃ to form a crystalline form; And Filtering the precipitated crystals and washing with an inert solvent. The method according to claim 4 or 5, wherein 1-5 equivalents of benzenesulfonic acid are reacted with 1 equivalent of ziprasidone. The method according to claim 4 or 5, wherein the inert solvent is acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, isopropyl ether, methylethylketone, dichloromethane, tetrahydrofuran, or a combination thereof. How to feature. A composition for treating schizophrenia or bipolar disorder-related mania, comprising the crystalline form of ziprasidone besylate according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

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