KR100843400B1 - Crystalline S---amlodipine maleic acid salt anhydrous and preparation method thereof - Google Patents

Abstract

The present invention relates to crystalline S-(-)-amlodipine maleic acid anhydride and a process for preparing the same. The crystalline S-(-)-amlodipine maleic acid anhydride according to the present invention is non-hygroscopic, has excellent physical and chemical properties such as solubility, thermal stability and light stability, has excellent formulation processability, and excellent long-term storage stability. .

Description

Crystalline S-(-)-amlodipine maleic acid anhydride and its preparation method {Crystalline S-(-)-amlodipine maleic acid salt anhydrous and preparation method

1 is a diagram showing an X-ray powder diffraction pattern of the crystalline S-(-)-amlodipine maleic acid anhydride according to Example 1 of the present invention.

2 is a diagram showing an X-ray powder diffraction pattern of the crystalline S-(-)-amlodipine maleic acid anhydride according to Example 2 of the present invention.

The present invention relates to crystalline S-(-)-amlodipine maleic acid anhydride and a process for preparing the same.

Amlodipine {3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate } Is a long acting calcium channel blocker and is useful for the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure.

Amlodipine is a chiral compound in which an asymmetric carbon is present. In general, the therapeutic effect as a drug on chiral compounds is better than pure isomeric compounds rather than isomeric mixtures, and also has different pharmacological profiles depending on the steric configuration of the isomeric compounds or their salt forms. In the case of amlodipine, there are two optical isomers of R-(+)-amlodipine and S-(-)-amlodipine, which have different drug activities. That is, R-(+)-amlodipine shows little activity as a calcium channel blocker but is not pharmacologically inactive and is a potent inhibitor of smooth muscle migration (US Pat. No. 6,080,761), which is active in the treatment or prevention of atherosclerosis. . In contrast, S-(-)-amlodipine exhibits a potent calcium channel blocking effect. An ideal method of using amlodipine, which is used as a calcium channel blocker, is the administration of S-(-)-amlodipine that is substantially free of R-(+)-amlodipine (US Pat. No. 6,057,344). U. S. Patent No. 6,291, 490 describes S-(-)-amlodipine and states that the S-(-)-amlodipine can avoid the potential side effects of amlodipine in the form of racemic mixtures.

EP 89,167 also discloses salt forms in which amlodipine is formed from an acid that forms a nontoxic acid addition salt containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, It is described that it can be used in the form of salts such as fumarate, lactate, tartrate, citrate and gluconate.

The pharmaceutically acceptable salt of S-(-)-amlodipine has specific properties compared to the salts of racemic amlodipine. Most salts of racemic amlodipine rarely form hydrates in the form of anhydrides, while many salts of S-(-)-amlodipine have the form of hydrates.

Korean Patent Publication No. 10-2005-37498 discloses a hydrophilic S-(-)-amlodipine salt or a hydrate thereof and a pharmacological composition thereof, and the hydrate of the S-(-)-amlodipine salt is S-(- ) -Amlodipine Benzenesulfonic Acid Dihydrate, S-(-)-Amlodipine Acetate Monohydrate, S-(-)-Amlodipine Aspartic Acid Dihydrate, S-(-)-Amlodipine Tartaric Acid Dihydrate, S-(-)-Amlodipine Sulfate Dihydrate, S-(-)-amlodipine hydrobromic acid monohydrate.

In addition, Korean Patent Publication No. 10-2004-23474 describes S-(-)-amlodipine nicotinate crystalline dihydrate and a method for preparing the same.

S-(-)-amlodipine salts must have good physical and chemical properties in order to be used for pharmaceutical use. Physical and chemical properties that are easy to formulate are 1) non-hygroscopic, 2) high solubility, 3) heat stable, 4) light stable, and 5) low tack, and the acid used to form the salt has pharmacological properties. It should not have any problem, should be harmless to human body, and should be easy in manufacturing process.

S-(-)-amlodipine, which is currently commercially available in Korea, is a benzenesulfonic acid salt, S-(-)-amlodipine besylate, which has a form of 2.5 hydrate (content: 7.5%). However, due to the high water content, S-(-)-amlodipine besylate salts require precise moisture control during manufacture, and careful attention to climate is required when manufacturing finished products or when storing raw materials for long periods of time.

As described above, the salt in the form of a hydrate may have a different degree of hydration due to the difference in the manufacturing process, which makes it difficult to manage the process or hassles a disadvantage, sometimes has hygroscopicity, and has a lower thermal stability than an anhydride form. . In addition, there is a disadvantage that exhibits high tackiness during formulation processing.

In general, since the salts of S-(-)-amlodipine are mostly present in the form of hydrates, the formulation may be difficult due to the above problems.

Therefore, there is a need for a study on the pharmaceutical salt of S-(-)-amlodipine having excellent physical properties that solve the above problems.

Thus, the present inventors while studying to solve the problem that the salt of S-(-)-amlodipine is mostly in the form of a hydrate, it is not easy to formulate processing, while S-(-)-amlodipine, hygroscopic and corrosive Since it is not harmful to human body, it is safe to manufacture and easy to handle, and the crystalline S-(-)-amlodipine maleic acid anhydride was prepared by reacting maleic acid which is useful for mass production. The crystalline S-(-)-amlodipine maleic acid anhydride is non-hygroscopic, and has excellent physical and chemical properties such as solubility, thermal stability and light stability, excellent formulation processability, and long-term storage stability. Was completed.

The present invention seeks to provide crystalline S-(-)-amlodipine maleic acid anhydride and a method for preparing the same.

The present invention provides crystalline S-(-)-amlodipine maleic acid anhydride represented by the following formula (1).

Crystalline S-(-)-amlodipine maleic acid anhydride according to the present invention is 8.7 °, 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, 19.22 ° , 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 °, 26.14 °, 27.08 °, 28.36 °, 28.98 °, 30.20 °, 35.22 °, 37.18 °, or 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, 19.22 °, 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 °, 26.14 °, 27.08 °, 28.36 °, 28.98 °, 30.20 ° , A diffraction X-ray peak at a diffraction angle of 35.22˚, 37.18˚, characterized in that the melting point is 165 ~ 170 ℃.

The crystalline S-(-)-amlodipine maleic acid salt anhydride according to the present invention shows more than equivalent non-hygroscopic, thermal stability compared to commercially available S-(-)-amlodipine besylate salt 2.5 hydrate (trade name: levension), It has an equivalent solubility characteristic at pH 1.2 to 6.8, and in particular, it is very excellent in light stability and excellent in processability of the preparation, and therefore, it can be expected to be stable in storage according to long-term use as a therapeutic agent for hypertension. The light stability means that when stored for 4 weeks while being exposed to a light source at 25 ℃, it exhibits a content of 90% or more, preferably 95% or more, more preferably 98% or more.

The crystalline S-(-)-amlodipine maleic acid salt anhydride according to the present invention has a solubility characteristic equivalent to the hydrate of S-(-)-amlodipine besylate salt 2.5 hydrate, despite being nonhygroscopic and anhydride.

The present invention also provides a process for the preparation of crystalline S-(-)-amlodipine maleic acid anhydride.

The preparation method according to the present invention is characterized in that crystalline S-(-)-amlodipine maleic acid anhydride is obtained by reacting S-(-)-amlodipine with maleic acid in an inert solvent or distilled water (H ₂ O), It is represented by Reaction Scheme 1 below.

Maleic acid used in the manufacturing method of the present invention is a safe acid that is widely used in pharmaceuticals, and is very safe to use. It is a stable colorless solid, hygroscopic and noncorrosive, and is not harmful to the human body. It can be used easily.

Inert solvents used in the preparation method of the present invention include acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, and the like, and may be used as a single solvent or a mixed solvent thereof. In addition, the S-(-)-amlodipine maleic acid salt prepared using distilled water as a reaction solvent is uniquely anhydride and is obtained as a non-hygroscopic property unlike those known through the prior art.

Referring to the production method of the present invention in detail.

First, S-(-)-amlodipine is dissolved in an inert solvent or distilled water. At this time, the amount of inert solvent or distilled water corresponds to the volume (ml number) of 2-50 times the weight (g) of S-(-)-amlodipine, preferably the volume (ml number) of 2-15 times. Use the amount you say. 1 to 2 equivalents, preferably 1.02 to 1.2 equivalents, of maleic acid was added to 1 equivalent of S-(-)-amlodipine, and 30 minutes at a reaction temperature of -5 to 30 ° C, preferably 15 to 25 ° C. Reaction for ˜5 hours, preferably 1 to 3 hours to prepare crystalline S-(-)-amlodipine maleic acid anhydride.

Crystalline S-(-)-amlodipine maleic anhydride salt anhydride can be prepared in a high yield of 85% or more by the preparation method of the present invention as described above.

Crystalline S-(-)-amlodipine maleic acid anhydride prepared by the preparation method of the present invention is non-hygroscopic, has excellent physical and chemical properties such as solubility, thermal stability, and light stability, and is excellent in processability of preparation. Excellent storage stability

The present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases, including the crystalline S-(-)-amlodipine maleic acid anhydride prepared above.

The composition of the present invention may contain one or more known active ingredients having a prophylactic or therapeutic effect of a cardiovascular disease together with crystalline S-(-)-amlodipine maleic acid anhydride.

The composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, as necessary. And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dose of the crystalline S-(-)-amlodipine maleic acid anhydride is about 0.1-20 mg / kg, preferably about 2.5-5.0 mg / kg, more preferably administered once or several times a day. Do.

The composition of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers for the prevention or treatment of cardiovascular diseases.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example  One  : Non-hygroscopic  Crystalline S-(-)- Amlodipine Maleic acid  Preparation of Salt Anhydrides

13 g (0.0316 mol) of S-(-)-amlodipine was added to 120 ml of ethanol and dissolved. 3.86 g (1.05 equiv) of maleic acid was added thereto, stirred at 25 ° C. for 2 hours, and the resulting solid was filtered. The resulting solid was washed with 20 mL of ethanol, filtered and then vacuum dried at 40 ° C. As a result, 16.86 g of S-(-)-amlodipine maleic acid anhydride was obtained as a white crystalline solid (yield: 91%, moisture: 0.07%).

The prepared crystalline S-(-)-amlodipine maleic acid anhydride was measured by the diffraction angle by X-ray powder diffraction method, melting point measurement method (Metalization Point Method 1 or European Pharmacopoeia of the 8th general test method of the Pharmacopoeia According to the capillary measurement method of the fourth modified melting point measurement method, the melting range was measured by observing the measurement range at 50 to 200 ° C. and the temperature increase rate at 1 ° C./min.

The X-ray powder diffraction pattern of the prepared crystalline S-(-)-amlodipine maleic acid anhydride is shown in Figure 1, its elemental analysis results and melting point is shown below.

-Diffraction angle: 8.7 °, 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, 19.22 °, 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 ˚, 26.14˚, 27.08˚, 28.36˚, 28.98˚, 30.20˚, 35.22˚, 37.18˚,

Elemental Analysis: C ₂₄ H ₂₉ ClN ₂ O ₉ [found (C: 54.95, H: 5.62, N: 5.38, O: 27.58), theoretical (C: 54.91, H: 5.57, N: 5.34, O: 27.43) ],

-Melting point: 165 ~ 170 ℃.

Example  2  : Non-hygroscopic  Crystalline S-(-)- Amlodipine Maleic acid  Preparation of Salt Anhydrides

13 g (0.0316 mol) of S-(-)-amlodipine was added to 60 ml of distilled water, followed by slurrying, followed by addition of 3.86 g (1.05 equivalents) of maleic acid and stirring. While completely dissolved at 25 ° C., the crystals precipitate after stirring for 2 hours. The crystals were filtered, washed with 20 ml of distilled water, and dried in vacuo at 40 ° C. to obtain 14.7 g of S-(-)-amlodipine maleate (yield: 87%, moisture: 0.08%).

The X-ray powder diffraction pattern of the prepared crystalline S-(-)-amlodipine maleic acid anhydride is shown in Figure 2, the elemental analysis results and melting point are as follows.

-Diffraction angle: 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, 19.22 °, 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 °, 26.14 ˚, 27.08˚, 28.36˚, 28.98˚, 30.20˚, 35.22˚, 37.18˚,

Elemental analysis: C ₂₄ H ₂₉ ClN ₂ O ₉ [found (C: 54.96, H: 5.55, N: 5.33, O: 27.61), theoretical (C: 54.91, H: 5.57, N: 5.34, O: 27.43) ],

-Melting point: 165 ~ 170 ℃.

compare Example  One  : S-(-)- Amlodipine Besylate  2.5 Preparation of Hydrates

S-(-)-amlodipine was prepared according to the method described in US Pat. No. 6,046,338. In addition, S-(-)-amlodipine besylate 2.5 hydrate was prepared using S-(-)-amlodipine according to the method described in Korean Patent Publication No. 10-2005-37498.

Experimental Example  One  : Hygroscopicity Test

The crystalline S-(-)-amlodipine maleic acid anhydride prepared in Examples 1 and 2, and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to various humidity conditions at 25 ° C. Water content (% moisture in KF) was measured under 25%, 60%, 75%, 95%).

The results are shown in Table 1.

Storage condition (relative humidity) 25% 60% 75% 95% Storage period Early 1 week later 1 week later 1 week later 1 week later Example 1 0.07% 0.07% 0.08% 0.09% 0.14% Example 2 0.08% 0.07% 0.09% 0.09% 0.11% Comparative Example 1 7.8% 7.55% 7.6% 7.85% 7.9%

As shown in Table 1, the crystalline S-(-)-amlodipine maleic acid salt anhydride of Example 1 prepared using an inert solvent as the reaction solvent according to the present invention, and an implementation prepared using distilled water as the reaction solvent The crystalline S-(-)-amlodipine maleic acid anhydride of Example 2 did not exhibit hygroscopicity at various humidity conditions. On the other hand, the commercially available S-(-)-amlodipine besylate 2.5 hydrate of Comparative Example 1 exhibited an aspect in which the initial high moisture content was maintained.

Experimental Example  2  Solubility Test

The crystalline S-(-)-amlodipine maleic acid anhydride prepared in Example 1, and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were solubilized at 25 ° C. under various pH solution conditions. Was measured.

The results are shown in Table 2.

menstruum Example 1 Comparative Example 1 Remarks Distilled water 2.72 2.51 PH buffer solution according to Korean Pharmacopoeia pH 1.2 4.71 3.12 pH 4.0 2.95 2.94 pH 6.8 1.94 1.39

(Unit: mg / ml)

As shown in Table 2, the solubility of the crystalline S-(-)-amlodipine maleic acid anhydride (Example 1) of the present invention in distilled water and various pH buffers was S-(-)-amlodipine besylate 2.5 hydrate. The solubility characteristic equivalent to the solubility of (Comparative Example 1) was shown.

Experimental Example  3  : Thermal Stability Test

1. Thermal stability in the solid state

The crystalline S-(-)-amlodipine maleic acid anhydride prepared in Example 1, and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to an accelerated test at 60 ° C. It was.

<HPLC analysis conditions>

Detector: ultraviolet 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.

The results are shown in Table 3.

Early 1 week 2 weeks 4 Weeks Example 1 99.8% 99.8% 99.8% 99.7% Comparative Example 1 99.6% 99.6% 99.7% 99.6%

(Unit is HPLC content%)

As shown in Table 3, the crystalline S-(-)-amlodipine maleic anhydride salt of the present invention (Example 1), and S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) were both 60 There was little change in content in the accelerated test at ℃. Therefore, it can be seen that the crystalline S-(-)-amlodipine maleic acid salt anhydride of the present invention is excellent in thermal stability with temperature to the same extent as S-(-)-amlodipine besylate salt 2.5 hydrate.

2. Thermal stability in aqueous solution

In order to determine the thermal stability in the aqueous solution, the crystalline S-(-)-amlodipine maleic acid anhydride prepared in Example 1, and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 After dissolving each in distilled water, and then stored at 25 ℃ for 4 weeks to observe the change in content. 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 the stability test in the shading aqueous solution, the crystalline S-(-)-amlodipine maleic anhydride salt of the present invention (Example 1), and S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) were all There were no degradation products and no change in content could be observed.

Experimental Example  4  : Optical Stability Test

The crystalline S-(-)-amlodipine maleic anhydride anhydride prepared in Example 1, and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to ICH guidelines at 25 ° C. It was stored for 4 weeks with exposure to a light source in a photostability chamber. 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.

The results are shown in Table 4.

Early 25 ℃, 4 weeks storage Content (HPLC) Content (HPLC) Example 1 99.5% 92.9% Comparative Example 1 99.2% 79.6%

As shown in Table 4, the crystalline S-(-)-amlodipine maleic anhydride salt of the present invention (Example 1) had little change in content and white initial sample exposed to the light source. On the other hand, S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) changed the surface exposed to the light source from the initial white to yellow and the content was reduced from 99.2% to 79.6%.

Therefore, it can be seen that the crystalline S-(-)-amlodipine maleic acid anhydride according to the present invention has excellent light stability. Since high blood pressure medications are long-term products, light stability is very important.

The crystalline S-(-)-amlodipine maleic acid anhydride according to the present invention is non-hygroscopic, has excellent physical and chemical properties such as solubility, thermal stability and light stability, has excellent formulation processability, and excellent long-term storage stability. .

Claims (8)

8.7 °, 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, 19.22 °, 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 °, 26.14 ° , 27.08 °, 28.36 °, 28.98 °, 30.20 °, 35.22 °, diffraction angle of 37.18 °, or 11.66 °, 13.04 °, 13.28 °, 15.52 °, 16.34 °, 16.74 °, 17.42 °, 18.26 °, 18.82 °, It has diffraction X-ray peaks at diffraction angles of 19.22 °, 22.10 °, 22.42 °, 23.08 °, 23.76 °, 24.70 °, 26.14 °, 27.08 °, 28.36 °, 28.98 °, 30.20 °, 35.22 ° and 37.18 ° Crystalline S-(-)-amlodipine maleic acid anhydride represented by the following general formula (1) whose melting point is 165-170 degreeC. <Formula 1>

delete delete The crystal of claim 1, wherein the crystalline S-(-)-amlodipine maleic acid salt anhydride of Formula 1 is obtained by reacting S-(-)-amlodipine with maleic acid in an inert solvent or distilled water (H ₂ O). Process for the preparation of the sexual S-(-)-amlodipine maleic acid anhydride. <Formula 1>

The crystalline S-(-)-amlodipine male according to claim 4, wherein the inert solvent is at least one selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane and isopropyl ether. Process for the preparation of ic acid anhydride The method of claim 4, wherein the maleic acid is used in an amount of 1 to 2 equivalents based on 1 equivalent of S-(-)-amlodipine. A pharmaceutical composition for the prevention or treatment of cardiovascular diseases selected from the group consisting of hypertension, angina pectoris and congestive heart disease comprising crystalline S-(-)-amlodipine maleic anhydride of claim 1. The pharmaceutical composition for preventing or treating cardiovascular diseases of claim 7, wherein the composition is formulated as a tablet, capsule, granule, pill, or injection.

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