KR100596369B1 - Crystalline organic acid salt of amlodipine - Google Patents

Abstract

The present invention relates to a novel organic acid salt of amlodipine of crystalline form having excellent physicochemical properties, a preparation method thereof, and a pharmaceutical composition comprising the same.

Amlodipine, Organic Salts

Description

Crystalline organic acid salt of amlodipine

1 is an X-ray powder diffractogram of crystalline amlodipine adipic acid salt according to the present invention.

Figure 2 is a scanning micrograph of amlodipine adipic acid salt of the crystalline form according to the present invention.

The present invention provides amlodipine (2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxyl of formula It relates to a novel organic acid salt of acid 3-ethyl 5-methyl ester), a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.

Amlodipine is a therapeutic agent for hypertension that has a calcium channel blocking effect and is a salt form formed from an acid that forms a nontoxic acid addition salt containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, Mali. It has been disclosed that it can be used in the form of salts such as ate, fumarate, lactate, tartrate, citrate and gluconate (European Patent Publication No. 89,167). In addition, U. S. Patent No. 6,291, 490 discloses S-(-)-amlodipine, and discloses that S-(-)-amlodipine can avoid the potential side effects of amlodipine in the form of racemic mixtures.

In addition, U.S. Patent No. 4,879,303 and Korean Patent Publication No. 1989-3375 have disclosed amlodipine besylate salts, and the amlodipine besylate salt has a higher solubility compared to hydrochloride, acetate salt, mesylate salt, and the like. It is disclosed that physicochemical criteria such as (2) excellent stability, (3) non-hygroscopicity, and (4) processability into tablet formulations are met.

However, the current commercially available amlodipine besylate has a relatively low solubility at pH 1-7.4, it was required to find an alternative salt having improved solubility characteristics. In addition, amlodipine besylate has a problem that many decomposition products are found because the stability to light is very weak.

In addition, benzenesulfonic acid used in the manufacturing process of amlodipine besylate is a corrosive, harmful substance, which is disadvantageous for industrial use, and because it is a highly hygroscopic acid, special safety management during transportation, transportation, and use is important. In addition, there is a disadvantage in that it is used as a wet and sticking property containing about 90% acid and about 10% water (WO1999 / 52873). In addition, even though benzenesulfonic acid in the form of ammonium salt is used to overcome this problem, it is described that a process of additionally absorbing and deactivating it is necessary because it is accompanied by generation of toxic gas ammonia in the amlodipine besylate manufacturing process. WO1999 / 52873).

Therefore, the present inventors have conducted research to develop a novel amlodipine salt that can solve the above problems, the crystalline form of amlodipine adipic acid (adipic acid salt of amlodipine) has excellent physical and chemical properties (non-hygroscopic) , Heat stability, solubility, processability, light stability), as compared with the benzenesulfonic acid used in the production of amlodipine besylate, adipic acid is not harmful and non-corrosive, and it is hygroscopic and easy to handle. It was found useful and completed the present invention.

It is therefore an object of the present invention to provide crystalline amlodipine adipic acid salts.                         

It is also an object of the present invention to provide a method for preparing the amlodipine adipic acid salt of the above crystalline form.

It is also an object of the present invention to provide a pharmaceutical composition containing the above-mentioned amlodipine adipic acid salt as an active ingredient.

In order to achieve the above object of the present invention, the present invention provides the crystalline amlodipine adipic acid salt.

The present invention also provides a method for preparing adipine salts of amlodipine, which comprises reacting amlodipine with adipic acid in an inert solvent.

The present invention also provides a pharmaceutical composition for treating ischemic heart disease or hypertension, comprising a therapeutically effective amount of crystalline form of amlodipine adipic acid salt and a pharmaceutically acceptable diluent or carrier.

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

The present invention relates to amlodipine adipic acid salt of amlodipine of formula (2).

Crystalline amlodipine adipic acid salt according to the present invention is at least 10.85 °, 13.02 °, 15.10 °, 16.31 °, 18.21 °, 21.69 °, 23.70 when measured by X-ray powder diffraction method. Crystalline amlodipine adipic acid salts having diffraction X-ray peaks at diffraction angles of ˚, 26.18 °, and 28.74 ° are preferred, and crystalline amlodipine adies having the X-ray powder diffraction pattern of FIG. Finate is more preferred. In addition, the crystalline form of amlodipine adipic acid was measured by melting point measurement method (capillary measurement method of melting point measurement method 1 of the 8th general test method of the Korean Pharmacopoeia or melting method of 4th European Pharmacopoeia), the measurement range is 50 to When observing 200 degreeC and a temperature increase rate at 1 degree-C / min, it is preferable that the said crystal form amlodipine adipic acid salt has melting | fusing point of 164 degreeC-168 degreeC.

Amlodipine adipic acid salt of the present invention has a non-hygroscopicity, formulation processability and thermal stability equivalent to or higher than that of commercially available amlodipine besylate, and has better solubility characteristics at pH 1 to 8, in particular, to light The stability of the organic acid is significantly higher than that of other known organic acids, and it can be expected that the storage stability according to long-term use as a treatment for hypertension.

The present invention provides adipic acid salts of ammodipine which are photostable, wherein the term "photostable" is at least 90%, preferably at least 95%, and more, when stored at 25 ° C. for 4 weeks with exposure to sunlight. Preferably refers to a content of 98% or more.

The present invention includes a process for the preparation of amlodipine adipic acid salt of the above crystalline form. That is, the present invention includes a method for preparing crystalline amlodipine adipic acid salt which comprises reacting amlodipine and adipic acid in an inert solvent. If this is represented by the reaction scheme, it is shown in the following scheme 1.

Adipic acid used in the production method according to the present invention is an acid that is also used as a food additive, is a stable colorless solid, hygroscopic and non-corrosive, is not harmful and is safe in manufacturing and easy to handle, so it can be easily used for mass production. .

Inert solvents usable in the production process of the present invention include ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, n-hexane, isopropyl ether and the like. On the other hand, in view of the tendency of non-hygroscopicity to be different depending on the solvent used, methanol is more preferable because not only a product having excellent nonhygroscopicity can be obtained, but also a crystalline product can be easily obtained.

1 to 2 equivalents of adipic acid, preferably 1.02 to 1.2 equivalents, may be added dropwise to 1 equivalent of amlodipine in the inert solvent, and may be reacted at a reaction temperature of -5 ° C to 30 ° C, preferably 0 ° C to 15 ° C. The reaction can be carried out for 30 minutes to 5 hours, preferably 1 to 3 hours.

By the production method of the present invention as described above, it is possible to produce a crystalline amlodipine adipic acid salt in a high yield of 90% or more.

The present invention includes a pharmaceutical composition for treating ischemic heart disease or hypertension comprising a therapeutically effective amount of crystalline form of amlodipine adipic acid and a pharmaceutically acceptable diluent or carrier.

The composition of the present invention may be formulated into parenteral formulations such as oral preparations such as granules, powders, solutions, tablets, capsules, or dry syrups, or injections, but is not limited thereto. 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 amlodipine adipic acid salt used in the composition of the present invention may be in the range of 2 to 10 mg per day as amlodipine, and the unit dosage form may be in the range of 3 to 16 mg. It may contain.

As the pharmaceutically acceptable diluent or 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 a coating base, high molecular materials, such as methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, 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%). .

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

Crystalline amlodipine adipic acid salts were prepared through the preparation method of the present invention, and known amlodipine salts were prepared as reference examples. Various physical properties of the prepared crystalline amlodipine adipic acid salt and known amlodipine salts were tested. In order to determine the formulation, tablets, capsules and aqueous solutions were prepared. In addition, physical properties such as hygroscopicity, solubility, thermal stability, and light stability were compared with amlodipine besylate.

Reference Example 1. Preparation of Amlodipine Besylate

Amlodipine was prepared according to the method disclosed in Korean Patent Publication No. 87-809. In addition, amlodipine besylate was prepared according to the method disclosed in Korean Patent Publication No. 95-7228.

Reference Example 2. Preparation of Amlodipine Para-Toluene Sulfonate

20 g of para-toluenesulfonic acid was dissolved in 100 ml of methanol. 40 g of amlodipine prepared in Reference Example 1 was added dropwise with 500 ml of methanol, followed by stirring at 23 ° C. for 3 hours. The resulting solid was filtered, washed with 100 ml each of methanol and normal-hexane and dried in vacuo.

Reference Example 3. Preparation of Amlodipine Hydrochloride

12 ml of concentrated hydrochloric acid was dissolved in 100 ml of methanol. 54 g of amlodipine prepared in Reference Example 1 was added dropwise in 500 ml of methanol, and then stirred at 23 ° C. for 3 hours. The resulting solid was filtered, washed with 100 ml each of methanol and normal-hexane and dried in vacuo.

Example 1 Preparation of Amlodipine Adipinate in Crystalline Form

4.85 g (1.05 equivalents) of adipic acid and 10 ml of methanol were added and dissolved in a 1 L three-necked flask. A solution of 13 g (0.0316 mol) of amlodipine dissolved in 65 ml of methanol was added dropwise, stirred at 23 ° C. for 2 hours, cooled to 7 ° C., stirred for 1 hour, and filtered. The resulting solid was washed with 15 ml of methanol and 15 ml of acetone at 5 ° C., filtered and then vacuum dried at 35 ° C. As a result, 15.5 g (yield: 91%) of amlodipine adipic acid salt was obtained as a white crystalline solid.

Table 1 shows the results of elemental analysis of the obtained crystalline amlodipine adipic acid salt.

Table 1.

Elemental Analysis (C ₂₆ H ₃₅ ClN ₂ O ₈ )  unit(%) Found  C: 55.9 H: 6.4 N: 5.1 O: 24.1 Theory  C: 56.3 H: 6.4 N: 5.1 O: 26.0

According to the melting point measurement method (melting point measurement method 1 of the 8th general test method of the Korean Pharmacopoeia; capillary measurement method of the 4th revision of the European Pharmacopoeia), the measurement range was 50-200 ° C and the temperature increase rate was 1 ° C / min. In this case, the melting point of the crystalline amlodipine adipic acid salt was 164 ° C to 168 ° C.

In addition, X-ray powder diffraction of the crystalline amlodipine adipic acid salt prepared above was carried out. The results are shown in Figure 1, it was confirmed that the diffraction X-ray peak at the diffraction angle of 10.85 °, 13.02 °, 15.10 °, 16.31 °, 18.21 °, 21.69 °, 23.70 °, 26.18 °, and 28.74 °. In addition, a scanning micrograph of the crystalline amlodipine adipic acid salt prepared above is shown in FIG. 2.

Example 2 Preparation of Tablets Containing Crystalline Amlodipine Adipinate

Next, the ingredients shown in Table 2 were mixed to prepare tablets containing the crystalline amlodipine adipic acid salt.

Table 2.

 ingredient  Content (in 1 tablet)  Crystalline Amlodipine Adipinate  5.0 mg equivalent as amlodipine  Low Substitution Hydroxypropyl Cellulose  65 mg  Microcrystalline cellulose  120 mg  Sodium starch glycolate  4 mg  Magnesium Stearate  2 mg

Each of the above components was mixed, compression-assembled using a roller compactor (manufacturer product), and the resulting granulated product was compressed using a tableting machine (manufactured by ERWEKA).

Example 3 Preparation of Tablets Containing Crystalline Amlodipine Adipinate

Next, the components shown in Table 3 were mixed to prepare tablets containing the crystalline amlodipine adipic acid salt.

Table 3.

 ingredient  Content (in 1 tablet)  Crystalline Amlodipine Adipinate  5.0 mg equivalent as amlodipine  Lactose  180 mg  Crospovidone  6mg  Polyvinylpyrrolidone K90  6mg  Sodium starch glycolate  4mg  Magnesium Stearate  2mg

Lactose, crospovidone, and polyvinylpyrrolidone K90 were used to prepare tableting mixed granules by fluid bed granulation (using SPIR A FLOW), and then the remaining ingredients were mixed and tableted using a tableting machine (ERWEKA). .

Example 4 Preparation of Capsules Containing Crystalline Amlodipine Adipinate

Next, the ingredients shown in Table 4 were mixed to prepare a capsule containing crystalline amlodipine adipic acid salt.

Table 4.

 ingredient  Content (in 1 capsule)  Crystalline Amlodipine Adipinate  5.0 mg equivalent as amlodipine  Low Substitution Hydroxypropyl Cellulose  65mg  Microcrystalline cellulose  120mg  Sodium starch glycolate  4mg  Magnesium Stearate  2mg

Each of the above components was mixed, compressed and granulated using a roller compactor (manufactured by Co., Ltd.), and the resulting granules were filled into hard capsules using a capsule filling machine (manufactured by Bosche).

Example 5 Preparation of Capsules Containing Crystalline Amlodipine Adipinate

Next, the components shown in Table 5 were mixed to prepare a capsule containing crystalline amlodipine adipic acid salt.

Table 5.

 ingredient  Content (in 1 capsule)  Crystalline Amlodipine Adipinate  5.0 mg equivalent as amlodipine  Lactose  180 mg  Crospovidone  6mg  Polyvinylpyrrolidone K90  6mg  Sodium starch glycolate  4mg  Magnesium Stearate  2mg

Lactose, crospovidone, and polyvinylpyrrolidone K90 were used to prepare mixed granules by fluid bed granulation (using SPIR A FLOW), and then the remaining ingredients were mixed and capsule filling machine (manufactured by Bosche) was used. Filled hard capsules.

Example 6 Hygroscopicity Test of Crystalline Amlodipine Adipinate

The water content (KF moisture%) of the amlodipine adipic acid salt of the crystalline form prepared in Example 1 and the amlodipine besylate prepared in Reference Example 1 were measured at 25 ° C. under various humidity conditions, and the results are shown in Table 6. .

Table 6.

Storage condition (relative humidity) 25% 60% 75% 95% Storage period Early 1 week later 1 week later 1 week later 1 week later Adipate 0.10% 0.10% 0.10% 0.14% 0.16% Besylate 0.14% 0.10% 0.09% 0.15% 0.17%

As shown in Table 6, the crystalline amlodipine adipate showed a nonhygroscopicity equivalent to or greater than amlodipine besylate at various humidity conditions. The hygroscopicity of less than 0.5% at 95% relative humidity is considered to be a salt that can be preferably used even when various formulations such as tablets, capsules, injections and the like.

Example 7 Solubility Test of Crystalline Amlodipine Adipinate

The solubility of amlodipine adipate of crystalline form prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 was measured at 25 ° C. under various pH solution conditions, and the results are shown in Table 7 below. In Table 7, the solubility is the solubility in mg / ml in terms of amlodipine.

Table 7.

menstruum Salt used Remarks Adipinate (mg / ml) Besylate (mg / ml) Distilled water 1.53 1.29 pH 2.0 3.68 1.29  Ionic Strength 0.2 Buffer at 25 ° C pH 4.0 2.27 1.32 pH 6.0 2.30 1.28 pH 7.0 4.48 0.64 pH 7.4 2.79 1.35 pH 8.0 2.35 1.25

As shown in Table 7, the solubility of the crystalline amlodipine adipic acid salt in distilled water and various pH buffers has about two times better solubility characteristics in most pH ranges except distilled water than the solubility of amlodipine besylate. As a result, higher bioavailability is expected.

Example 8 Stability Test of Crystalline Amlodipine Adipinate

1.Thermal Stability of Amlodipine Adipinate in Crystalline Form in the Solid State

With the amlodipine adipic acid salt and amlodipine besylate of crystalline form prepared in Example 1, an accelerated test was carried out at 60 ℃, the results are summarized in Table 8.

Amlodipine besylate used as a comparative test sample was prepared and used according to Reference Example 1.

Table 8.

Early 1 week 2 weeks 4 Weeks Adipate 99.8% 99.8% 99.7% 99.7% Besylate 99.6% 99.6% 99.5% 99.5%

(Unit is HPLC content%)

HPLC analysis conditions were as follows:

Detector: UV absorbance (wavelength 237 nm)

Column: Octadecyl Silica Gel C18 (4.6 mm x 150 mm, 5 μm)

Mobile phase: Potassium dihydrogen phosphate monobasic (0.03M): Methanol = 4: 6 (volume)

Flow rate: 1.5 ml / min

As shown in Table 8, the crystalline amlodipine adipate had little content change in the accelerated test at 60 ° C with amlodipine besylate. Therefore, it was found that the adipine acid salt of amlodipine has excellent chemical stability with temperature along with the besylate salt.

2. in aqueous solution Stability of Crystalline Amlodipine Adipinate

In order to determine the stability of the solution, the crystalline amlodipine adipic acid salt prepared in Example 1 and the amlodipine besylate prepared by the method of Reference Example 1 was dissolved in distilled water, and then shielded at 25 ℃ and stored for 4 weeks The change in content was observed. At this time, the content change was observed in the same manner as the HPLC analysis conditions used for the thermal stability test in the solid state.

As a result of stability test in shading aqueous solution, both crystalline amlodipine adipic acid salt and amlodipine besylate had no degradation products, and no significant content change could be observed.

Example 9 Photostability Test of Crystalline Amlodipine Adipinate

In this example, for the light stability test, the crystalline amlodipine adipic acid salt prepared in Example 1 was used, and the amlodipine besylate and other known alternative salts prepared by the methods of Reference Examples 1 to 3 at 25 ° C. And stored for 4 weeks while exposed to daylight. The results are shown in Table 9 below.

Table 9.

Early 25 ℃, daylight, 4 weeks storage Content (HPLC) Content (HPLC) Adipate 99.5% 99.1% Besylate 99.2% 82.5% Tosylate 99.2% 72.0% Hydrochloride 99.0% 60.5%

As shown in Table 9 above, the amlodipine besylate had changed from the initial white to the yellow surface exposed to sunlight. The crystalline amlodipine adipate did not change in the white initial sample even when exposed to sunlight. The change in content (HPLC) was measured to measure the light stability, and the HPLC analysis conditions were the same as the thermal stability observation conditions. Since the antihypertensive drug is a long-term product, photostability is very important, and the crystalline amlodipine adipic acid salt was found to have better light stability than amlodipine besylate.

Amlodipine adipic acid salt of the present invention has excellent physicochemical properties (non-hygroscopicity, stability, solubility, processability), and in particular, excellent light stability, it is easy to move in the patient body and excellent long-term storage.

In addition, adipic acid used in salt preparation is not harmful and non-corrosive, and it is also industrially useful because it is not hygroscopic and easy to handle.

Claims (10)

Amlodipine adipic acid salt in crystalline form, measured by X-ray powder diffraction method, at least 10.85 °, 13.02 °, 15.10 °, 16.31 °, 18.21 °, 21.69 °, A crystalline amlodipine adipic acid salt having a diffraction X-ray peak at diffraction angles of 23.70 °, 26.18 °, and 28.74 °, wherein the melting point is 164 ° C to 168 ° C. delete The crystalline amlodipine adipic acid salt according to claim 1, having an X-ray powder diffraction pattern of FIG. delete The amlodipine adipic acid salt according to claim 1, which is a photo stable crystalline form. delete delete A pharmaceutical composition for treating ischemic heart disease or hypertension, comprising the crystalline amlodipine adipic acid salt according to any one of claims 1, 3 and 5 and a pharmaceutically acceptable diluent or carrier. 9. A pharmaceutical composition according to claim 8 in the form of a tablet or capsule. 9. A pharmaceutical composition according to claim 8 in the form of a liquid or injectable.

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