WO2008060093A1

WO2008060093A1 - Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof

Info

Publication number: WO2008060093A1
Application number: PCT/KR2007/005706
Authority: WO
Inventors: Il Hwan Cho; Yong Sik Youn; Seog Beom Song; Dong Kwon Lim
Original assignee: CJ CheilJedang Corp
Current assignee: CJ CheilJedang Corp
Priority date: 2006-11-14
Filing date: 2007-11-14
Publication date: 2008-05-22
Anticipated expiration: 2009-05-14
Also published as: KR20080043489A; KR100843400B1

Abstract

Disclosed are an anhydrate of crystalline S-(-)-amlodipine maleate and a preparation method thereof. The anhydrate of crystalline S-(-)-amlodipine maleate exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, and photo- stability, and is superior in formulation processability and long-term storage safety.

Description

CRYSTALLINE S-(-)-AMLODIPINE MALEIC ACID SALT ANHYDRIDE AND PREPARATION METHOD THEREOF

Technical Field

[1] The present invention relates to an anhydrate of crystalline S-(-)-amlodipine maleate and a method of preparing the same. Background Art

[2] Amlodipine, the IUPAC Name of

3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-cholorophenyl)-l,4-dihydro-6-methyl -3,5-pyridinedicarboxylate, is a long-acting calcium channel blocker useful in the treatment of cardiovascular diseases, such as hypertension, congestive heart failure, etc.

[3] Amlodipine is a chiral compound with a chiral center. In general, pure stereoisomers are known to have better therapeutic effects than racemic mixtures. Futhermore, 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 (U. S. Pat. 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 (U.S. Pat. No. 6,057,344). U.S. Pat. No. 6,291,490 also discloses S-(-)-amlodipine, teaching that S-(-)-amlodipine avoids the adverse effect of amlodipine in racemic mixtures.

[4] 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.

[5] The pharmaceutically acceptable salts of S-(-)-amlodipine have unique physical properties comparing with salts of racemic amlodipine. 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.

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

[7] Korean Patent Laid-Open Publication No. 10-2004-23474 discloses crystalline S-

(-)-amlodipine nicotinate dihydrate and a preparation method thereof.

[8] For use in pharmaceutical formulations, S-(-)-amlodipine salts must meet physical and chemical standards: l)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.

[9] Currently commercially available is S-(-)-amlodipine besylate, which is in the form of 2.5 hydrates (water content : 7.5%). But S-(-)-amlodipine besylate requires precious water control during preparation procedure due to its high water content, and scrupulous care for preparation of amlodipine formulation or long-term storage of raw materials depending upon weather. Disclosure of Invention Technical Problem

[10] 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.

[11] Existing in the form of hydrates, most currently used S-(-)-amlodipine salts are difficult to formulate into pharmaceutical preparations.

[12] 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.

[13] 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 anhydrated of crystalline S-(-)-amlodipine maleate, produced by the reaction of S- (-)-amlodipine with maleic acid which is non-hygroscopic, non-corrosive and easy to manage. An anhydrate of crystalline S-(-)-amlodipine maleate exhibits excellent physical an dchemical properties including non-hygroscopicity, solubility, thermal stability, and photostability, and is superior in formulation processability and long-term storage safety. Technical Solution

[14] It is an object of the present invention to provide an anhydrate of crystalline S-

(-)-amlodipine maleate, and a method for preparing the same.

Brief Description of the Drawings [15] FIG. 1 is an XRD(X-ray diffraction) diagram of the anhydrate of crystalline S-

(-)-amlodipine maleate according to Example 1 of the present invention. [16] FIG. 2 is an XRD(X-ray diffraction) diagram of the anhydrate of crystalline S-

(-)-amlodipine maleate according to Example 2 of the present invention.

Best Mode for Carrying Out the Invention [17] In accordance with an aspect thereof, the present invention provides an anhydrate of crystalline S-(-)-amlodipine maleate, represented by the following Chemical Formula

1:

[18]

[19] <Chemical Formula 1 >

[20]

[21] The anhydrate of crystalline S-(-)-amlodipine maleate in accordance with the present invention has X-ray diffraction peaks at diffraction angles of 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° and 37.18° or at diffraction angles of 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° and 37.18°, and has a melting point of 165-17O⁰C.

[22] Compared to commercially available S-(-)-amlodipine besylate 2.5 hydrate (brand name: Levotension), the anhydrate of crystalline S-(-)-amlodipine maleate in accordance with the present invention has an equivalent or higher level of non- hygroscopicity and thermal stability, and exhibits an equivalent level of solubility at pH 1.2-6.8. Particularly, being far superior in photostability and formulation pro- cessability, the anhydrate of crystalline S-(-)-amlodipine maleate 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 25°C 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. [23] Anhydrous and non-hygroscopic as it is, the compound of the present invention has equivalent solubility to that of S-(-)-amlodipine besylate 2.5 hydrate. [24] [25] In accordance with another aspect thereof, the present invention provides a method for preparing an anhydrate of crystalline S-(-)-amlodipine maleate. [26] As illustrated by the following Reaction Scheme 1, the preparation method according to the present invention features a reaction between S-(-)-amlodipine and maleic acid in an inert solvent or distilled water (H O) to afford an anhydrate of crystalline S-(-)-amlodipine maleate. [27] <Reaction Scheme 1>

[28]

[29] Maleic acid, the material for the compound of the present invention, is currently widely used for drugs and medicines and is a stable colorless powder that is neither hygroscopic nor caustic. In addition, maleic 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.

[30] Examples of the inert solvent suitable for the preparation method of the present invention include acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, and mixtures thereof. Further, S-(-)-amlodipine maleate, prepared using distilled water as a reaction solvent, is anhydrous and non-hygroscopic, unlike the fact known through the prior art.

[31] A detailed description is given of the preparation method of the present invention, below.

[32] First, S-(-)-amlodipine is dissolved in an inert solvent or distilled water. The inert solvent or distilled water is used in a volumetric amount (ml) 2-50 times the weight (g) of the S-(-)-amlodipine used, and preferably in a volumetric amount (ml) 2-15 times the weight (g) of the S-(-)-amlodipine used. To this solvent is added maleic 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 - 25°C for 0.5 - 5 hours, and preferably 1 - 3 hours, affords an anhydrous, crystalline S-(-)-amlodipine maleate.

[33] Through the preparation method of the present invention, the anhydrate of crystalline S-(-)-amlodipine maleate can be produced at a yield of 85% or higher.

[34] The anhydrate of crystalline S-(-)-amlodipine maleate produced by the method of the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, thermal stability, photostability, formulation pro- cessability and long-term storage safety.

[35]

[36] 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 anhydrate of crystalline S-(-)-amlodipine maleate prepared by the method of the present invention.

[37] In addition to the anhydrate of crystalline S-(-)-amlodipine maleate, the pharmaceutical composition of the present invention may comprise at least one known active ingredient useful in the prevention or treatment of cardiovascular diseases.

[38] 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, an anti-bacterial agent, etc., may be added to the composition. Also, the pharmaceutical composition of the present invention may optionally be formulated with a diluent, a surfactant, a binder and/or a lubricant, into an injection, such as an aqueous solution, a suspension, an emulsion, etc., a tablet, a capsule, a granule or a pill. 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 and/or ingredients.

[39] 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, route and method of administrations, excretion rate, severity of illness, and the like. The anhydrate of crystalline S-(-)-amlodipine maleate 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.

[40] 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/or a biological response regulator. [41] 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. Mode for the Invention

[42] EXAMPLE 1: Preparation of Anhydrate of Non-Hygroscopic Crystalline S-

(-)-Amlodipine Maleate

[43] 13g (0.0316mol) of S-(-)-amlodipine was dissolved in 120 ml of ethanol. To this solution was added 3.86g (1.05 eq.) of maleic acid, followed by stirring at 25⁰C for 2 hours to afford a precipitate. After filtration, the precipitate was washed and purified with 20 ml of ethanol and dried at 4O⁰C in a vacuum to produce 16.86 g of an anhydrate of S-(-)-amlodipine maleate as a white crystalline solid (yield: 91%, water content: 0.07%).

[44] The anhydrate of crystalline S-(-)-amlodipine maleate was analyzed to determine diffraction angles using an X-ray powder diffraction method, and measured for melting point with an increase in temperature at a rate of l°C/min from 50 to 200⁰C through a melting point measurement method (Melting Point Method I of General Test Methods in Korean Pharmacopeia D or Melting Point-Capillary Method of European Pharmacopoeia IV).

[45] The X-ray diffraction spectrum of anhydrate of the above produced crystalline S-

(-)-amlodipine maleate is shown in FIG. 1, and its eleme4ntal analysis data and melting point are given as follows.

[46] - Diffraction Angles: 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°,

[47] - Elemental Analysis for C H ClN O [found (C: 54.95, H: 5.62, N: 5.38,

^J 24 29 2 9

O: 27.58), calculated (C: 54.91, H: 5.57, N: 5.34, O: 27.43)],

[48] - Melting point: 165-17O⁰C.

[49]

[50] EXAMPLE 2: Preparation of Anhydrate of Non-Hygroscopic Crystalline S-

(-)-Amlodipine Maleate

[51] 13g (0.0316mol) of S-(-)-amlodipine was slurried with 60 ml of distilled water, followed by the addition of 3.86 g (1.05 eq.) of maleic acid thereto. Stirring for 2 hours formed a crystalline precipitate in the complete solution at a temperature of 25⁰C. After filtration, the crystalline precipitate was washed with 20 ml of distilled water and dried at 4O⁰C in a vacuum to afford 14.7 g of S-(-)-amlodipine maleate (yield: 89%, water content: 0.08%).

[52] The X-ray diffraction spectrum of anhydrate of the above produced crystalline S- (-)-amlodipine maleate is shown in FIG. 2, and its elemental analysis data and melting point are given as follows.

[53] - Diffraction Angles: 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°,

[54] - Elemental analysis for C H ClN O [found (C: 54.96, H: 5.55, N: 5.33,

24 29 2 9

O: 27.61), calculated (C: 54.91, H: 5.57, N: 5.34, O: 27.43)].

[55] - Melting point: 165-17O⁰C. [56] [57] Comparative Example 1: Preparation of S-(-)-Amlodipine Besylate 2.5 Hydrate

[58] S-(-)-amlodipine was prepared according to the method described in U. S. Pat. No. 6,046,338. S-(-)-amlodipine besylate 2.5 hydrate was prepared from S-(-)-amlodipine using the method disclosed in Korean Patent Laid-Open Publication No. 10-2005-37498.

[59] [60] EXPERIMENTAL EXAMPLE 1 : Hygroscopicity Test [61] The anhydrates of crystalline S-(-)-amlodipine maleate prepared in Examples 1 and 2, 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%).

[62] The results are summarized in Table 1, below. [63] Table 1

[64] [65] As shown in Table 1, the anhydrate of S-(-)-amlodipine maleate prepared using an inert solvent as a reaction solvent in Example 1 and the anhydrate of S-(-)-amlodipine maleate prepared using distilled water as a reaction solvent in Example 1 were 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.

[66] [67] EXPERIMENTAL 2: Solubility Test [68] The anhydrate of crystalline S-(-)-amlodipine maleate prepared in Example 1, and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were measured for solubility at 25⁰C under various pH conditions.

[69] The results are summarized in Table 2, below. [70] Table 2

[71] (Unit: mg/ml) [72] [73] As is understood from the data of Table 2, the solubility of the anhydrate of crystalline S-(-)-amlodipine maleate of the present invention (Example 1) was equivalent to that of S-(-)-amlodipine besylate 2.5 hydrate (Comparative Example 1) in distilled water and buffers over a wide range of pH values.

[74] [75] EXPERIMENTAL EXAMPLE 3: Thermal Stability Test [76] 1. Thermal Stability in Solid State [77] The anhydrate of crystalline S-(-)-amlodipine maleate 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.

[78] <HPLC Analysis Condition> [79] - Detector: UV absorbance (at 237 nm), [80] - Column: Octadecyl silica gel C18 (4.6mm x 150mm, 5D), [81] - mobile phase: Potassium dihydrogen phosphate monobasic (0.03 M): Methanol = 4: 6 (by volume)

[82] - Flow rate: 1.5 ml/min. [83] [84] The results are summarized in Table 3, below. [85] Table 3

[86] (Unit: HPLC content %) [87] [88] All of the anhydrate of crystalline S-(-)-amlodipine maleate of the present invention (Example 1) and the 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 6O⁰C acceleration test, suggesting that the anhydrate of crystalline S-(-)-amlodipine maleate of the present invention was as good in thermal stability as S-(-)-amlodipine besylate 2.5 hydrate.

[89] [90] 2. Thermal Stability in Aqueous Solution State [91] To evaluate the thermal stability of samples in aqueous solution state, the anhydrate of crystalline S-(-)-amlodipine maleate 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 25⁰C in the dark with the content thereof monitored. The observation was made under the same conditions as in the HPLC analysis for evaluating the thermal stability of samples in a solid state.

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

[93] [94] EXPERIMENTAL EXAMPLE 4: Photostability Test [95] The anhydrate of crystalline S-(-)-amlodipine maleate prepared in Example 1 and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were stored for 4 weeks at 25⁰C 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 thermal stability of samples.

[96] The results are given in Table 4, below. [97] Table 4

[98]

[99] As shown in Table 4, there were hardly any content and color changes observed in the anhydrate of crystalline S-(-)-amlodipine maleate whose initial color was white (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.

[100] Thus, the anhydrate of crystalline S-(-)-amlodipine maleate 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

[101] The anhydrate of crystalline S-(-)-amlodipine maleate 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

[1] An anhydrate of crystalline S-(-)-amlodipine maleate, represented by the following Chemical Formula 1 : <Chemical Formula 1>

[2] The anhydrate of crystalline S-(-)-amlodipine maleate according to claim 1, wherein the anhydrate has X-ray diffraction peaks at diffraction angles of 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° and 37.18°, with a melting point ranging from 165 to 17O⁰C.

[3] The anhydrate of crystalline S-(-)-amlodipine maleate according to claim 1, wherein the anhydrate has X-ray diffraction peaks at diffraction angles of 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° and 37.18°, with a melting point ranging from 165 to 17O⁰C.

[4] A method for preparing an anhydrate of crystalline S-(-)-amlodipine maleate of claim 1, represented by the following Chemical Formula 1, comprising a reaction between S-(-)-amlodipine and maleic acid in an inert solvent or distilled water (H

O):

[5] The method according to claim 4, wherein the inert solvent is selected from a group consisting of acetone, ethyl acetate, methanol, ethanol, isopropanol, ace- tonitrile, hexane, isopropyl ether and a combination thereof.

[6] The method according to claim 4, wherein the maleic acid is used in an amount of 1-2 equivalents per equivalent of S-(-)-amlodipine.

[7] A pharmaceutical composition for prevention or treatment of cardiovascular diseases, comprising the anhydrate of crystalline S-(-)-amlodipine maleate of claim 1 as an active ingredient.

[8] The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in a dosage form of a tablet, a capsule, a granule, a pill or an injection.