WO2008091085A1

WO2008091085A1 - Crystalline s-(-)-amlodipine orotate anhydrous and preparation method thereof

Info

Publication number: WO2008091085A1
Application number: PCT/KR2008/000366
Authority: WO
Inventors: Dong Kwon Lim; Yong Sik Youn; Seog Beom Song; Il Hwan Cho
Original assignee: Cj Cheiljedang Corporation
Priority date: 2007-01-23
Filing date: 2008-01-21
Publication date: 2008-07-31
Also published as: KR100840069B1

Abstract

Disclosed are crystalline S- (-) -amlodipine orotate anhydrous and a preparation method thereof. The crystalline S- (-) -amlodipine orotate anhydrous according to the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, and photostability, and is superior in formulation processability and long-term storage safety.

Description

[DESCRIPTION]

[invention Title]

CRYSTALLINE S- (-) -AMLODIPINE OROTATE ANHYDROUS AND PREPARATION METHOD THEREOF

[Technical Field]

The present invention relates to crystalline

S- (-) -amlodipine orotate anhydrous and a method of preparing the same.

[Background Art]

Amlodipine, the IUPAC Name of

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 useful in the treatment of cardiovascular diseases, such as angina pectoris, hypertension, and congestive heart failure.

Amlodipine is a racemic compound with a chiral center. In general, pure stereoisomers are known to have better therapeutic effects than racemic mixtures . Furthermore, chiral compounds tend to have different pharmacokinetic profiles, depending on the steric arrangement of the isomer compounds or their salts. There are two possible stereoisomers of amlodipine, because of its one chiral center, that is, R- (+) -amlodipine and (S- (-) -amlodipine, that are different from each other in pharmacokinetic profile.

The R- (+) -isomer of amlodipine is a potent inhibitor of smooth muscle cell migration despite its lack of calcium channel-blocking activity (US Patent No. 6,080,761) . It is useful for preventing and treating atherosclerosis. On the other hand, the

(S) - (-) -isomer of amlodipine is a potent calcium channel blocker.

For ideal use as a calcium channel blocker, amlodipine is administered in the form of S- (-) -amlodipine, substantially free of its (+) stereoisomer (US Patent No. 6,057,344) . US Patent No. 6,291,490 also discloses S- (-) -amlodipine, teaching that S- (-) -amlodipine avoids the adverse effect of amlodipine in racemic mixtures.

European Patent Publication No. 89,167 discloses an acid adduct as an example of a pharmaceutically acceptable amlodipine salt. The pharmaceutically acceptable acid adduct is formed from an acid that forms a nontoxic acid adduct including a pharmaceutically acceptable anion, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate or gluconate. As distinct from salts of racemic amlodipine, almost none of which form hydrates, pharmaceutically acceptable salts of

S- (-) -amlodipine are in the most part in the form of hydrates.

Korean Patent Publication No. 10-2005-37498 describes hydrophilic S- (-) -amlodipine salts or hydrates thereof and pharmaceutical compositions comprising the same. Examples of the hydrates of S- (-) -amlodipine salts include S- (-) -amlodipine benzenesulfonatedihydrate, S- (-) -amlodipine acetate monohydrate, S- (-) -amlodipine aspartate dihydrate, S- (-) -amlodipine tartrate dihydrate, S- (-) -amlodipine sulfate dihydrate, and S- (-) -amlodipine hydrobromide monohydrate.

Korean Patent Publication No. 10-2004-23474 discloses crystalline S- (-) -amlodipine nicotinate dihydrate and a preparation method thereof.

For use in pharmaceutical formulations, S- (-) -amlodipine salts must meet physical and chemical standards: 1) non-hygroscopicity, 2) high solubility, 3) high thermal stability, 4) high photostability and 5) low viscosity. In addition, requirements of acids suitable for use in pharmaceutically acceptable salts include non-pharmaceutical properties, harmlessness, and processing feasibility.

Currently commercially available is S- (-) -amlodipine besylate, which is in the form of 2.5 hydrate (water content: 7.5%) . The high water content requires precise water control and scrupulous care for the preparation and storage of S- (-) -amlodipine .

As such, salts in a hydrous form suffer from disadvantages in that they are difficult or inconvenient to manage because their hydration varies depending on processing conditions, are hygroscopic, and are inferior in thermal stability to those in anhydrous forms . When processed into pharmaceutical formulations , hydrous salts show high viscosity.

Existing in the form of hydrates, most currently used S- (-) -amlodipine salts are difficult to formulate into pharmaceutical preparations. Therefore, there is a need for pharmaceutical salts of S- (-) -amlodipine that are imparted with physical properties good enough to overcome the problems encountered in the prior art.

[Disclosure] [Technical Problem]

Leading to the present invention, intensive and thorough research into S- (-) -amlodipine salts, conducted by the present inventors, aiming to solve the problems encountered with hydrous forms of optically pure isomers, resulted in the finding that an anhydrate of S- (-) -amlodipine orotate, produced by the reaction of S- (-) -amlodipine with orotic acid, exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, and photostability, and is superior in formulation processability and long-term storage safety.

[Technical Solution]

It is an object of the present invention to provide crystalline S- (-) -amlodipine orotate anhydrous, and a method for preparing the same. [Description of Drawings]

FIG. 1 is an XRD diagram of crystalline S- (-) -amlodipine orotate anhydrous according to Example 1 of the present invention.

[Best Mode]

The present invention provides crystalline S- (-) -amlodipine orotate anhydrous represented by the following Formula 1. [Formula 1]

The crystalline S- (-) -amlodipine orotate anhydrous in accordance with the present invention has X-ray diffraction peaks at diffraction angles of 11.22°, 11.52°, 12.62°, 13.92°, 16.12°, 16.86°, 19.66°, 20.36°, 20.92°, 22.80°, 24.12°, 25.28°, 26.42°, 27.06°, 28.10°, 28.84°, 30.14°, 31.14°, and 32.18°, and a melting point of 223~225°C.

Compared to commercially available S- (-) -amlodipine besylate 2.5 hydrate (brand name: Levotension) , the crystalline S- (-) -amlodipine orotate anhydrous in accordance with the present invention has an equivalent or higher level of non-hygroscopicity and thermal stability, and exhibits equivalent solubility at pH 1.2-6.8. Particularly, being far superior in photostability and formulation processability, the crystalline S- (-) -amlodipine orotate anhydrous can be used as an anti-hypertensive that is required to be stored for a long period of time due to a prolonged term of use thereof. By the term "photostability" as used herein for the compound of the present invention, it is meant that after exposure to a light source at 25⁰C for 4 weeks, the content of the active ingredient remains 90% or more, preferably 95% or more, and more preferably 98% or more of its activity.

Non-hygroscopic and anhydrous as it is, the compound of the present invention has equivalent solubility to S- (-) -amlodipine besylate 2.5 hydrate.

In accordance with another aspect thereof, the present invention provides a method for preparing an anhydrate of crystalline S- (-) -amlodipine orotate. As illustrated by the following Reaction Scheme 1, the preparation method according to the present invention features a reaction between S- (-) -amlodipine and orotic acid in an inert organic solvent or distilled water (H₂O) to afford crystalline S- (-) -amlodipine orotate anhydrous. [Reaction Scheme 1]

Orotic acid, the material for the compound of the present invention, is a safe acid widely used in medicaments and is a stable colorless powder that is neither hygroscopic nor caustic. In addition, orotic acid is sufficiently harmless to the body to be safe for use in pharmaceutical preparations and sufficiently convenient to handle to be applicable in the mass production of pharmaceutical preparations.

Examples of the inert organic solvent suitable for the preparationmethod of the present invention include acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, and t-butyl methyl ether, and they may be used alone or in a mixed solvent thereof. In addition, the use of distilled water as a solvent affords nonhygroscopic, anhydrous S- (-) -amlodipine orotate, unlike in the prior art. A detailed description is given of the preparation method of the present invention, below.

First, S- (-) -amlodipine is dissolved in an inert organic solvent or distilled water. The inert organic solvent or distilled water is used in a volumetric amount (ml) 5~30 times the weight (g) of the S- (-) -amlodipine used, and preferably in a volumetric amount (ml) 10~20 times the weight (g) of the S- (-) -amlodipine used. To this solvent is added orotic acid in an amount of 1~2 equivalents, and preferably 1.02~1.2 equivalents per equivalent of S- (-) -amlodipine . Reaction at -5 - 30⁰C, preferably at 15 ~ 25⁰C for 0.5 - 5 hours, and preferably 1 ~ 3 hours, affords crystalline S- (-) -amlodipine orotate anhydrous.

Through the preparation method of the present invention, the crystalline S- (-) -amlodipine orotate anhydrous can be produced at a yield of 85% or higher. The crystalline S- (-) -amlodipine orotate anhydrous produced by the method of the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, photostability, formulation processability and long-term storage safety. In accordance with a further aspect thereof, the present invention provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases, comprising as an active ingredient the crystalline S- (-) -amlodipine orotate anhydrous prepared by the method of the present invention. In addition to the crystalline S- (-) -amlodipine orotate anhydrous, the pharmaceutical composition of the present invention may comprise at least one known active ingredient useful in the prevention or treatment of cardiovascular diseases.

For dosage forms, the pharmaceutical composition of the present invention may be formulated in combination with at least one pharmaceutically acceptable vehicle. Examples of the pharmaceutically acceptable vehicle include saline, sterile water, Ringer's solution, buffered saline, a dextrose solution, a maltodextrin solution, glycerol, ethanol and combinations thereof . If necessary, a conventional additive, such as an antioxidant, a buffer, and an anti-bacterial agent, may be added to the composition. Also, the pharmaceutical composition of the present inventionmay optionally be formulated with a diluent, a dispersing agent, a surfactant, a binder and a lubricant, into an injection, such as an aqueous solution, a suspension, and an emulsion, a tablet, acapsule, agranuleor apill . Furthermore, the formulation of the pharmaceutical composition of the present invention may be conducted according to methods known in the art, such as that described in Remington's Pharmaceutical Science (most recent edition) , Mack Publishing Company, Easton PA, depending on the disease or ingredients.

The pharmaceutical composition of the present invention may be administered orally or non-orally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) at a dose depending on various factors including the patient' s weight, age, gender, state of health, diet, administration time, administration route, excretion rate, severity of illness, and the like. The crystalline S- (-) -amlodipine orotate anhydrous may be administered in a single dose or in several doses per day with a daily dose ranging from 0.1 to 20 mg/kg, and preferably from 2.5 to 5.0 mg/kg.

For the prevention or treatment of cardiovascular diseases, the pharmaceutical composition of the present invention may be used alone or in combination with other therapies, including surgical therapy, hormonal therapy, chemical therapy, and a biological response regulator.

[Mode for Invention]

A better understanding of the present invention may be obtained through the following examples, which are set forth to illustrate, but are not to be construed as the limit of the present invention.

EXAMPLE 1: Preparation of crystalline S- (-) -amlodipine orotate anhydrous

13 g (0.0316 mol) of S- (-) -amlodipine was dissolved in 260 ml of methanol. To this solution was added 5.8 g (1.05 eq.) of orotic acid, and dissolved. Then, 130 ml of methanol was added thereto, followed by stirring at 25 °C for 2 hours to afford a precipitate. After filtration, the precipitate was washed and purified with 20 ml of methanol, and dried in a vacuum at 4O⁰C to produce 16.0 g of an anhydrate of S- (-) -amlodipine orotate as a white crystalline solid (yield: 85%, water content: 0.07%) .

The crystalline S- (-) -amlodipine orotate anhydrous was analyzed to determine diffraction angles using an X-ray powder diffractionmethod, andmeasured for melting point with an increase in temperature at a rate of l°C/min from 50 to 200° C through a melting point measurement method (Melting Point Method I of General Test Methods in Korean Pharmacopeia VIII or Melting Point-Capillary Method of European Pharmacopoeia IV) . The X-ray diffraction spectrum of the crystalline S- (-) -amlodipine orotate anhydrous according to the present invention is shown in FIG. 1, and its elemental analysis data and melting point are given as follows. - Diffraction Angles: 11.22°, 11.52°, 12.62°, 13.92°, 16.12°, 16.86°, 19.66°, 20.36°, 20.92°, 22.80°, 24.12°, 25.28°, 26.42°, 27.06°,, 28.10°, 28.84°, 30.14°, 31.14°, 32.18°,

- Elemental Analysis for C₂₅H₂₉CIN₄O₉ [found (%) (C: 53.45, H: 5.32, N: 9.98, O: 25.46), calculated (%) (C: 53.15, H: 5.17, N: 9.92, 0: 25.49)],

- m.p. : 223~225°C

EXAMPLE 2: Preparation of crystalline S- (-) -amlodipine orotate anhydrous 13 g (0.0316 mol) of S- (-) -amlodipine was slurried with 130 ml of distilled water, and 5.8 g (1.05 eq. ) of orotic acid was added thereto, and dissolved. 130 ml of distilled water was added thereto, followed by stirring at room temperature. The solution was left at 25°C until being fully dissolved, and stirred for 2 hours to afford a precipitate . After filtration, the crystalline precipitate was washed with 20 ml of distilled water and dried at 40°C in a vacuum to afford 16 g of S- (-) -amlodipine orotate anhydrous (yield: 85%, water content: 0.08%).

The X-ray diffraction spectrum of the crystalline S- (-) -amlodipine orotate anhydrous according to the present invention is the same as in FIG. 1, and its elemental analysis data and melting point are given as follows.

- Elemental analysis for C₂₅H₂₉ClN₄O₉ [found (%) (C: 53.25, H: 5.18, N: 9.98, 0: 25.48), calculated (%) (C: 53.15, H: 5.17, N: 9.92, 0: 25.49)],

- m.p.: 223~225°C

Comparative Example 1: Preparation of S- (-) -amlodipine Besylate 2.5 Hydrate S- (-) -amlodipine was prepared according to the method described in US Patent No. 6,046,338. S- (-) -amlodipine besylate 2.5 hydrate was prepared from S- (-) -amlodipine using the method disclosed in Korean Patent Publication No. 10-2005-37498.

EXPERIMENTAL EXAMPLE 1: Hygroscopicity Test

The crystalline S- (-) -amlodipine orotate anhydrous prepared in Example 1 and the S- (-) -amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were measured for water content (K. F. moisture%) at 25⁰C under various humidity conditions (25%, 60%, 75%, and 95%) .

The results are summarized in Table 1, below.

[Table i;

As shown in Table 1, the crystalline S- (-) -amlodipine orotate anhydrous according to the present invetion (Example 1) was found to show no hygroscopicity under various humidity conditions. In contrast, S- (-) -amlodipine besylate 2.5 hydrate of Comparative Example 1, which is currently commercially available, was high in water content from the beginning. Preferred formulation maintains its initial anhydrous form, and has non-hygroscopicity under a high humidity.

EXPERIMENTAL 2 : Solubility Test

The crystalline S- (-) -amlodipine orotate anhydrous prepared in Example 1 and the S- (-) -amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were measured for solubility at 25° C under various pH conditions.

The results are summarized in Table 2, below.

[Table 2\

Comparative

Solvents Example 1 Note Example 1

As is understood from the data of Table 2, the crystalline S- (-) -amlodipine orotate anhydrous of the present invention (Example 1) was found to have equivalent solubility to S- (-) -amlodipine besylate 2.5 hydrate (Comparative Example 1) in distilled water and under various pH conditions.

EXPERIMENTAL EXAMPLE 3: Stability Test 1. Thermal Stability in Solid State

The crystalline S- (-) -amlodipine orotate anhydrous prepared in Example 1 and the S- (-) -amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were subjected to an acceleration test at 6O⁰C. <HPLC Analysis Condition>

- Detector: UV absorbance (at 237 nm) ,

- Column: Octadecyl silica gel C18 (4.6mm x 150mm, 5/ΛΠ) ,

- Mobile phase: Potassium dihydrogen phosphate monobasic (0.03 M): Methanol = 4: 6 (by volume) - Flow rate: 1.5 ml/min. The results are summarized in Table 3, below.

[Table 3]

(Unit: % HPLC)

Both of the crystalline S- (-) -amlodipine orotate anhydrous of the present invention (Example 1) and S- (-) -amlodipine besylate 2.5 hydrate (Comparative Example 1), as seen in Table 3, were found to undergo little change in content as measured by the 60° C acceleration test, suggesting that the crystalline S- (-) -amlodipine orotate anhydrous of the present invention was as good in thermal stability as S- (-) -amlodipine besylate 2.5 hydrate .

2. Stability in Liquid State

To evaluate the stability of samples in a liquid state, the crystalline S- (-) -amlodipine orotate anhydrous prepared in Example 1 and the S- (-) -amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were dissolved in distilled water before storage for 4 weeks at 25° C in the dark with the content thereof monitored. The observation was made under the same conditions as in the HPLC analysis for evaluating the stability of samples in a solid state.

This stability test revealed that none of the crystalline S- (-) -amlodipine orotate anhydrous of the present invention (Example 1) and S- (-) -amlodipine besylate 2.5 hydrate (Comparative Example 1) were degraded. Also, no significant content changes were observed in any of them.

EXPERIMENTAL EXAMPLE 4: Photostability Test

The crystalline S- (-) -amlodipine orotate anhydrous prepared in Example 1 and the S- (-) -amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were stored for 4 weeks at 25 'C in a photostable chamber in accordance with ICH guidelines and were exposed to a light source. An observation was made of content (HPLC) change under the same conditions as in the HPLC analysis for evaluating the stability of samples.

The results are given in Table 4, below.

[Table 4]

As shown in Table 4, only a slight content change was observed in the crystalline S- (-) -amlodipine orotate anhydrous (Example 1) of the present invention. In contrast, S- (-) -amlodipine besylate 2.5 hydrate (Comparative Example 1) turned yellow from white with a decrease in content from 99.2% to 79.6% during exposure to the light source.

Thus, the crystalline S- (-) -amlodipine orotate anhydrous according to the present invention was confirmed to be highly photostable. Photostability is a very important factor for anti-hypertensives because they are generally administered over a long period of time.

[industrial Applicability] The crystalline S- (-) -amlodipine orotate anhydrous produced by the method of the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, and photostability, and is superior in formulation processability and long-term storage safety.

Claims

[CLAIMS]

1. Crystalline S- (-) -amlodipine orotate anhydrous, represented by the following Formula 1: <Formula 1>

2. The crystalline S- (-) -amlodipine orotate anhydrous according to claim 1, wherein the anhydrate has X-ray diffraction peaks at diffraction angles of 11.22°, 11.52°, 12.62°, 13.92°, 16.12°, 16.86°, 19.66°, 20.36°, 20.92°, 22.80°, 24.12°, 25.28°, 26.42°, 27.06°, 28.10°, 28.84°, 30.14°, 31.14° and 32.18°, with a melting point ranging from 223 to 225 °C.

3. A method for preparing crystalline S- (-) -amlodipine orotate anhydrous of claim 1 represented by the following Reaction Scheme 1, comprising a reaction between S- (-) -amlodipine and orotic acid in an inert organic solvent or distilled water: <Reaction Scheme 1>

4. The method according to claim 3, wherein the inert organic solvent is at least one selected froma group consisting of acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether and t-butyl methyl ether.

5. The method according to claim 3, wherein the orotic acid is used in an amount of 1~2 equivalents per equivalent of S- (-) -amlodipine .

6. A pharmaceutical composition for prevention or treatment of cardiovascular diseases, comprising the crystalline S- (-) -amlodipine orotate anhydrous of claim 1 as an active ingredient.

7. The pharmaceutical composition according to claim β, wherein the cardiovascular disease is angina pectoris, hypertension, or congestive heart failure.