KR100843401B1 - Crystalline S---amlodipine camsylate anhydrous and preparation method thereof - Google Patents

Abstract

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

Description

Crystalline S-(-)-amlodipine camsylate anhydride and its preparation method {Crystalline S-(-)-amlodipine camsylate anhydrous and preparation method

1 is a diagram showing an X-ray powder diffraction pattern of crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride according to Example 1 of the present invention.

2 is a diagram showing an X-ray powder diffraction pattern of crystalline S-(-)-amlodipine (1S)-(+)-10-camsylate anhydride according to Example 3 of the present invention.

The present invention relates to crystalline S-(-)-amlodipine camsylate 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-pyridine dicarboxylate } 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 requires precise moisture control during manufacturing, and careful attention to climate is required when manufacturing finished products or storing raw materials for a long time.

As described above, the salt in the form of the hydrate may have a different degree of hydration due to the difference in the manufacturing process, so that the process is difficult to manage or has a disadvantage, sometimes hygroscopic, and has a lower stability than the 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 thus crystalline S-(-)-amlodipine camsylate anhydride was prepared by reacting camphorsulfonic acid, which is useful for mass production. The crystalline S-(-)-amlodipine camsylate anhydride is non-hygroscopic, has excellent physical and chemical properties such as solubility, stability, and light stability, has excellent formulation processability, excellent long-term storage stability, and completes the present invention. It was.

The present invention seeks to provide crystalline S-(-)-amlodipine camsylate anhydride and methods for preparing the same.

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

The crystalline S-(-)-amlodipine camsylate anhydride according to the present invention comprises crystalline S-(-)-amlodipine (1R)-(-)-10-camylate anhydride and crystalline S-(-)-amlodipine ( 1S)-(+)-10-camsylate anhydride, including 7.80 °, 9.18 °, 9.56 °, 11.38 °, 12.78 °, 13.10 °, 13.84 °, 15.48 °, 15.68 °, 17.38 °, 18.94 °, 19.92 It has a diffraction X-ray peak at diffraction angles of ˚, 21.78˚, 23.16˚, 24.64˚, 25.86˚, and 26.44˚, and has a melting point of 94 ~ 99 ℃.

The crystalline S-(-)-amlodipine camsylate anhydride according to the present invention shows a non-hygroscopicity and stability equal to or higher than that of commercially available S-(-)-amlodipine besylate 2.5 hydrate (trade name: Revotent), pH 1.2 ~ It has a solubility characteristic equal to or higher than 6.8, and in particular, the light stability is very excellent and the formulation processability is excellent, so storage stability with long-term use as a therapeutic agent for hypertension can be expected. 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 camsylate anhydride according to the present invention, although non-hygroscopic and anhydrous, has more than equivalent solubility properties compared to the hydrate, S-(-)-amlodipine besylate 2.5 hydrate.

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

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

Camposulfonic acid used in the manufacturing method of the present invention is a safe acid widely used in pharmaceuticals, is a stable colorless solid, hygroscopic and non-corrosive, is not harmful to the human body, it is safe to manufacture and easy to handle, and therefore easy to mass production. Can be used. Since the camphorsulfonic acid exists as an optical isomer, (1R)-(-)-10-camposulfonic acid or (1S)-(+)-10-camposulfonic acid was used.

Thus, the S-(-)-amlodipine camsylate according to the present invention refers to a compound in the form of a salt obtained by reacting S-(-)-amlodipine with one of the camphorsulfonic acids.

Inert organic solvents used in the preparation method of the present invention include acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, t-butyl methyl ether, and the like, or a single solvent or a mixed solvent thereof. Can be used as In addition, S-(-)-amlodipine camsylate 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 organic solvent or distilled water. At this time, the amount of inert organic solvent or distilled water is 5 to 50 times the volume (ml number) relative to the weight (g) of S-(-)-amlodipine, preferably 8 to 16 times the volume (ml number). Use that amount. 1 to 2 equivalents of (1R)-(-)-10-camposulfonic acid or (1S)-(+)-10-camposulfonic acid to 1 equivalent of S-(-)-amlodipine, preferably 1.02. ˜1.2 equivalents are added and reacted for 30 minutes to 5 hours, preferably 1 to 3 hours at a reaction temperature of −10 to 50 ° C., preferably 15 to 30 ° C., to provide crystalline S-(-)-amlodipine camsylate. Anhydride is prepared.

Crystalline S-(-)-amlodipine camsylate anhydride can be prepared in a high yield of 80% or more by the preparation method of the present invention as described above.

The crystalline S-(-)-amlodipine camsylate anhydride prepared by the preparation method of the present invention is non-hygroscopic, has excellent physical and chemical properties such as solubility, stability, and light stability, has excellent formulation processability, and long-term storage stability. This is excellent.

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

The composition of the present invention may contain at least one known active ingredient having a prophylactic or therapeutic effect of a cardiovascular disease together with crystalline S-(-)-amlodipine camsylate 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 camsylate anhydride is about 0.1 to 100 mg / kg, preferably about 2.5 to 10 mg / kg, and more preferably administered once to several times a day. .

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  Crystalline S-(-)- Amlodipine  (1R)-(-)-10- Camsylate  Preparation of Anhydride

13 g (0.0316 mol) of S-(-)-amlodipine was added to 120 ml of isopropanol and dissolved. 6.96 g (1.05 equiv) of (1R)-(-)-10-camposulfonic acid was added thereto to dissolve it, 200 ml of t-butyl methyl ether was added thereto, stirred at 25 ° C. for 2 hours, and the resulting solid was filtered. It was. The resulting solid was washed with 50 ml of t-butyl methyl ether, filtered and then dried in vacuo at 40 ° C. As a result, 16.7 g of S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride was obtained as a white crystalline solid (yield: 84%, moisture: 0.15%).

The prepared crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride was measured for the diffraction angle by X-ray powder diffraction method, melting point measurement method (KEPCO General Test Method The melting point was measured by observing the measuring range of 50-200 ° C. and the temperature increase rate at 1 ° C./min according to the method of measuring the melting point of the first melting method or the European Pharmacopoeia Fourth Amendment.

The X-ray powder diffraction pattern of the crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride prepared above is shown in FIG. 1, and the results of elemental analysis and melting point thereof are shown below.

-Diffraction angle: 7.80˚, 9.18˚, 9.56˚, 11.38˚, 12.78˚, 13.10˚, 13.84˚, 15.48˚, 15.68˚, 17.38˚, 18.94˚, 19.92˚, 21.78˚, 23.16˚, 24.64˚, 25.86 ˚, 26.44˚,

Elemental Analysis: C ₃₀ H ₄₂ ClN ₂ O ₉ S [A found (%) (C: 56.11, H: 6.59, N: 4.36, O: 22.42), Theoretical (%) (C: 56.30, H: 6.62, N : 4.30, O: 22.50)],

Melting Point: 94 ~ 99 ℃.

Example  2  Crystalline S-(-)- Amlodipine  (1R)-(-)-10- Camsylate  Preparation of Anhydride

13 g (0.0316 mol) of S-(-)-amlodipine was added to 200 ml of distilled water, followed by slurrying. Then, 6.96 g (1.05 equiv) of (1R)-(-)-10-camposulfonic acid was added thereto and stirred at room temperature. After completely dissolved, the mixture was stirred at 25 ° C. for 2 hours to precipitate crystals. The crystals were filtered, washed with 20 ml of distilled water, and dried in vacuo at 40 ° C. to obtain 16.62 g of S-(-)-amlodipine (1R)-(-)-10-camylate anhydride (yield: 83%, moisture: 0.34%).

Elemental analysis results and melting points of the crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride prepared above are as follows.

Elemental Analysis: C ₃₀ H ₄₂ ClN ₂ O ₉ S [A found (%) (C: 56.11, H: 6.59, N: 4.36, O: 22.42), Theoretical (%) (C: 56.22, H: 6.65, N : 4.32, O: 22.55)],

Melting Point: 94 ~ 99 ℃.

Example  3  Crystalline S-(-)- Amlodipine  (1S)-(+)-10- Camsylate  Preparation of Anhydride

White crystals were prepared in the same manner as in Example 1, except that (1S)-(+)-10-camposulfonic acid was used instead of (1R)-(-)-10-camphorsulfonic acid in Example 1. 16.8 g of crystalline S-(-)-amlodipine (1S)-(+)-10-camsylate anhydride, which is a sexual solid, was obtained (yield: 84%, moisture: 0.20%).

The X-ray powder diffraction pattern of the prepared crystalline S-(-)-amlodipine (1S)-(+)-10-camsylate anhydride is shown in FIG. 2, and the results of elemental analysis and melting point thereof are shown below.

Elemental analysis: C ₃₀ H ₄₂ ClN ₂ O ₉ S [observed (%) (C: 56.11, H: 6.59, N: 4.36, O: 22.42), theoretical (%) (C: 56.21, H: 6.58, N : 4.40, O: 22.45)],

Melting Point: 94 ~ 99 ℃.

Example  4  Crystalline S-(-)- Amlodipine  (1S)-(+)-10- Camsylate  Preparation of Anhydride

White crystals were prepared in the same manner as in Example 2, except that (1S)-(+)-10-camposulfonic acid was used instead of (1R)-(-)-10-camposulfonic acid in Example 2. 16.63 g of crystalline S-(-)-amlodipine (1S)-(+)-10-camsylate anhydride was obtained as a solid (yield: 83%, moisture: 0.25%).

Elemental analysis results and melting points of the crystalline S-(-)-amlodipine (1S)-(+)-10-camsylate anhydride prepared above are shown below.

Elemental analysis: C ₃₀ H ₄₂ ClN ₂ O ₉ S [observed (%) (C: 56.11, H: 6.59, N: 4.36, O: 22.42), theoretical (%) (C: 56.46, H: 6.68, N : 4.42, O: 22.54)],

Melting Point: 94 ~ 99 ℃.

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 camsylate anhydride prepared in Examples 1 and 3, and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to various humidity conditions (25 %, 60%, 75%, 95%), and the water content (KF moisture%) was measured.

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 0.15% 0.14% 0.15% 0.15% 0.21% Example 3 0.20% 0.22% 0.25% 0.30% 0.34% Comparative Example 1 7.8% 7.55% 7.6% 7.85% 7.9%

As shown in Table 1, crystalline S-(-)-amlodipine (1R)-(-)-10-camylate anhydride (Example 1), and crystalline S-(-)-amlodipine according to the present invention ( 1S)-(+)-10-camsylate anhydride (Example 3) 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. Pharmaceutically preferred forms are more preferably in the form of drugs that do not absorb moisture even in high humidity environments, while initially maintaining the form of anhydrides.

Experimental Example  2  Solubility Test

Crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride prepared in Example 1, crystalline S-(-)-amlodipine (1S)-(prepared in Example 3 The solubility of +)-10-camsylate anhydride, and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 was measured at 25 ° C. under various pH solution conditions.

The results are shown in Table 2.

menstruum Example 1 Example 3 Comparative Example 1 Remarks Distilled water 4.34 4.30 2.51 PH buffer solution according to Korean Pharmacopoeia pH 1.2 26.01 25.43 3.12 pH 4.0 24.89 22.87 2.94 pH 6.8 1.24 1.25 1.39

(Unit: mg / ml)

As shown in Table 2, the crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride (Example 1) and crystalline S- of the present invention in distilled water and buffers of various pH. The solubility of (-)-amlodipine (1S)-(+)-10-camsylate anhydride (Example 3) is equal to or higher than the solubility of S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) Characteristics.

Experimental Example  3  : Stability Test

1. Stability in the solid state

Crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride prepared in Example 1, crystalline S-(-)-amlodipine (1S)-(prepared in Example 3 +)-10-campylate anhydride and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to a harsh test at 60 ° C.

<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 99.7% 99.7% 99.7% 99.6% Example 3 99.7% 99.7% 99.7% 99.7% Comparative Example 1 99.6% 99.6% 99.7% 99.6%

(Unit is HPLC content%)

As shown in Table 3, crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride of the present invention (Example 1), crystalline S-(-)-amlodipine (1S) Both-(+)-10-camsylate anhydride (Example 3) and S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) showed little content change in the harsh test at 60 ° C. Accordingly, it can be seen that the crystalline S-(-)-amlodipine camsylate anhydride of the present invention is excellent in temperature stability to the same extent as S-(-)-amlodipine besylate 2.5 hydrate.

2. Stability in aqueous solution

In order to determine the stability in the aqueous state, crystalline S-(-)-amlodipine (1R)-(-)-10-camylate anhydride prepared in Example 1, crystalline S- (prepared in Example 3 -)-Amlodipine (1S)-(+)-10-camsylate anhydride, and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1, respectively, were dissolved in distilled water, and then shaded at 25 ° C. Stored for weeks to observe changes in content. At this time, the content change was observed in the same manner as the HPLC analysis conditions used for the stability test in the solid state.

As a result of stability test in shading aqueous solution, crystalline S-(-)-amlodipine (1R)-(-)-10-camylate anhydride (Example 1) of the present invention, crystalline S-(-)-amlodipine (1S )-(+)-10-camsylate anhydride (Example 3) and S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) were all free of degradation products and no change in content was observed. .

Experimental Example  4  : Optical Stability Test

Crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride prepared in Example 1, crystalline S-(-)-amlodipine (1S)-(prepared in Example 3 +)-10-camsylate anhydride, and S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were exposed to a light source at 25 ° C. in a photostability chamber suitable for ICH guidelines. Stored for 4 weeks. The change in content (HPLC) was measured to measure the light stability, and the HPLC analysis conditions were the same as the stability observation conditions.

The results are shown in Table 4.

Early 25 ℃, 4 weeks storage Content (HPLC) Content (HPLC) Example 1 99.7% 91.9% Example 3 99.7% 91.4% Comparative Example 1 99.2% 79.6%

As shown in Table 4, crystalline S-(-)-amlodipine (1R)-(-)-10-camsylate anhydride (Example 1) and crystalline S-(-)-amlodipine (1S) of the present invention. -(+)-10-camsylate anhydride (Example 3) showed little change in content with the initial sample of white 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 camsylate anhydride according to the present invention is very excellent in light stability. Since high blood pressure medications are long-term products, light stability is very important.

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

Claims (9)

7.80 °, 9.18 °, 9.56 °, 11.38 °, 12.78 °, 13.10 °, 13.84 °, 15.48 °, 15.68 °, 17.38 °, 18.94 °, 19.92 °, 21.78 °, 23.16 °, 24.64 °, 25.86 °, 26.44 ° Crystalline S-(-)-amlodipine camsylate anhydride represented by the following Chemical Formula 1, having a diffraction X-ray peak at a diffraction angle of, and having a melting point of 94 to 99 ° C. <Formula 1>

The crystalline S-(-)-amlodipine camsylate anhydride according to claim 1, wherein the crystalline S-(-)-amlodipine camsylate anhydride is crystalline S-(-)-amlodipine (1R)-(-)-10-camylate anhydride or crystalline S-(-)- Crystalline S-(-)-amlodipine camsylate anhydride, characterized in that it is amlodipine (1S)-(+)-10-camsylate anhydride. delete Represented by Scheme 1 below, by reacting S-(-)-amlodipine and camphorsulfonic acid in an inert organic solvent or distilled water (H ₂ O) to obtain crystalline S-(-)-amlodipine camsylate anhydride A process for preparing crystalline S-(-)-amlodipine camsylate anhydride according to claim 1. <Scheme 1>

The crystalline S-(-)-according to claim 4, wherein the camphorsulfonic acid is (1R)-(-)-10-camposulfonic acid or (1S)-(+)-10-camposulfonic acid. Process for the preparation of amlodipine camsylate anhydride. The crystalline S according to claim 4, wherein the inert organic solvent is at least one selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, and t-butyl methyl ether. Method for preparing-(-)-amlodipine camsylate anhydride. The method of claim 4, wherein the camphor sulfonic 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 the crystalline S-(-)-amlodipine camsylate anhydride of claim 1. The composition of claim 8, wherein the composition is formulated in a form selected from the group consisting of tablets, capsules, granules, pills and injections.

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