WO2008060093A1 - Anhydride de sel d'acide s-(-)-amlodipine maléique cristallin, et son procédé de préparation - Google Patents

Anhydride de sel d'acide s-(-)-amlodipine maléique cristallin, et son procédé de préparation Download PDF

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Publication number
WO2008060093A1
WO2008060093A1 PCT/KR2007/005706 KR2007005706W WO2008060093A1 WO 2008060093 A1 WO2008060093 A1 WO 2008060093A1 KR 2007005706 W KR2007005706 W KR 2007005706W WO 2008060093 A1 WO2008060093 A1 WO 2008060093A1
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WIPO (PCT)
Prior art keywords
amlodipine
crystalline
anhydrate
amlodipine maleate
maleate
Prior art date
Application number
PCT/KR2007/005706
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English (en)
Inventor
Il Hwan Cho
Yong Sik Youn
Seog Beom Song
Dong Kwon Lim
Original Assignee
Cj Cheiljedang Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cj Cheiljedang Corporation filed Critical Cj Cheiljedang Corporation
Publication of WO2008060093A1 publication Critical patent/WO2008060093A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to an anhydrate of crystalline S-(-)-amlodipine maleate and a method of preparing the same.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Korean Patent Laid-Open Publication No. 10-2004-23474 discloses crystalline S-
  • 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.
  • requirements of acids suitable for use in pharmaceutically acceptable salts include non-pharmaceutical properties, harmlessness, and processing feasibility.
  • 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.
  • hydrous salts show high viscosity.
  • (-)-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.
  • FIG. 1 is an XRD(X-ray diffraction) diagram of the anhydrate of crystalline S-
  • FIG. 2 is an XRD(X-ray diffraction) diagram of the anhydrate of crystalline S-
  • the present invention provides an anhydrate of crystalline S-(-)-amlodipine maleate, represented by the following Chemical Formula
  • 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°
  • 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.
  • 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.
  • 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
  • the present invention provides a method for preparing an anhydrate of crystalline S-(-)-amlodipine maleate.
  • 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.
  • 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.
  • 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.
  • 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.
  • S-(-)-amlodipine maleate prepared using distilled water as a reaction solvent, is anhydrous and non-hygroscopic, unlike the fact known through the prior art.
  • 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.
  • maleic acid in an amount of 1-2 equivalents, and preferably 1.02-1.2 equivalents per equivalent of S- (-)-amlodipine. Reaction at -5 - 30 0 C, preferably at 15 - 25°C for 0.5 - 5 hours, and preferably 1 - 3 hours, affords an anhydrous, crystalline S-(-)-amlodipine maleate.
  • the anhydrate of crystalline S-(-)-amlodipine maleate can be produced at a yield of 85% or higher.
  • 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.
  • 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.
  • the pharmaceutical composition of the present invention may comprise at least one known active ingredient useful in the prevention or treatment of cardiovascular diseases.
  • the pharmaceutical composition of the present invention may be formulated in combination with at least one pharmaceutically acceptable vehicle.
  • the pharmaceutically acceptable vehicle include saline, sterile water, Ringer's solution, buffered saline, a dextrose solution, a maltodextrin solution, glycerol, ethanol and combinations thereof.
  • a conventional additive such as an antioxidant, a buffer, an anti-bacterial agent, etc., may be added to the composition.
  • 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.
  • a diluent such as an aqueous solution, a suspension, an emulsion, etc., a tablet, a capsule, a granule or a pill.
  • 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.
  • 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.
  • 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.
  • therapies including surgical therapy, hormonal therapy, chemical therapy, and/or a biological response regulator.
  • (-)-amlodipine maleate is shown in FIG. 1, and its eleme4ntal analysis data and melting point are given as follows.
  • 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.
  • EXPERIMENTAL EXAMPLE 1 Hygroscopicity Test
  • 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 25 0 C under various humidity conditions (25%, 60%, 75%, and 95%).
  • EXPERIMENTAL 2 Solubility Test
  • 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 25 0 C under various pH conditions.
  • 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 6O 0 C.
  • EXPERIMENTAL EXAMPLE 4 Photostability Test
  • 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 25 0 C in a photostable chamber in accordance with ICH guidelines and were exposed to a light source.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Dermatology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un anhydrate de maléate de S-(-)-amlodipine cristallin et son procédé de préparation. L'anhydrate de maléate de S-(-)-amlodipine cristallin présente d'excellentes propriétés physiques et chimiques dont non-hygroscopicité, la solubilité, la stabilité thermique et la photostabilité ; son aptitude à un processus de formulation et de sécurité de stockage à long terme est supérieure.
PCT/KR2007/005706 2006-11-14 2007-11-14 Anhydride de sel d'acide s-(-)-amlodipine maléique cristallin, et son procédé de préparation WO2008060093A1 (fr)

Applications Claiming Priority (2)

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KR10-2006-0112111 2006-11-14
KR1020060112111A KR100843400B1 (ko) 2006-11-14 2006-11-14 결정성 ｓ-(-)-암로디핀 말레익산 염 무수물 및 이의제조방법

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2077994A1 (fr) * 2006-10-31 2009-07-15 CJ CheilJedang Corporation Sel d'acide adipique s-(-)-amlodipine cristallin anhydre et procédé d'élaboration
CN103006648A (zh) * 2012-12-17 2013-04-03 石药集团欧意药业有限公司 一种马来酸左旋氨氯地平药物活性组合物及其制备方法
CN103044314A (zh) * 2013-01-06 2013-04-17 先声药业有限公司 马来酸氨氯地平的制备方法
CN103058914A (zh) * 2012-12-17 2013-04-24 石药集团欧意药业有限公司 马来酸左旋氨氯地平晶型及其制备方法
CN111689894A (zh) * 2019-03-13 2020-09-22 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平晶型
CN112110850A (zh) * 2019-06-20 2020-12-22 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平新晶型
CN115974769A (zh) * 2022-11-29 2023-04-18 常州瑞明药业有限公司 一种马来酸左旋氨氯地平晶型及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053542A1 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Procede de preparation de maleate d'amlodipine
WO2003043989A1 (fr) * 2001-11-22 2003-05-30 Xitian Zhang Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques
WO2005049571A1 (fr) * 2003-11-20 2005-06-02 Council Of Scientific And Industrial Research Procede de preparation de sels chiraux d'amlodipine
KR20050122617A (ko) * 2004-06-25 2005-12-29 종근당바이오 주식회사 암로디핀 말레에이트의 개선된 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053542A1 (fr) * 2000-12-29 2002-07-11 Pfizer Limited Procede de preparation de maleate d'amlodipine
WO2003043989A1 (fr) * 2001-11-22 2003-05-30 Xitian Zhang Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques
WO2005049571A1 (fr) * 2003-11-20 2005-06-02 Council Of Scientific And Industrial Research Procede de preparation de sels chiraux d'amlodipine
KR20050122617A (ko) * 2004-06-25 2005-12-29 종근당바이오 주식회사 암로디핀 말레에이트의 개선된 제조방법

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2077994A1 (fr) * 2006-10-31 2009-07-15 CJ CheilJedang Corporation Sel d'acide adipique s-(-)-amlodipine cristallin anhydre et procédé d'élaboration
EP2077994A4 (fr) * 2006-10-31 2010-12-15 Cj Cheiljedang Corp Sel d'acide adipique s-(-)-amlodipine cristallin anhydre et procédé d'élaboration
US8362263B2 (en) 2006-10-31 2013-01-29 Cj Cheiljedang Corporation Crystalline S-(−)-amlodipine adipic acid salt anhydrous and preparation method thereof
CN103006648A (zh) * 2012-12-17 2013-04-03 石药集团欧意药业有限公司 一种马来酸左旋氨氯地平药物活性组合物及其制备方法
CN103058914A (zh) * 2012-12-17 2013-04-24 石药集团欧意药业有限公司 马来酸左旋氨氯地平晶型及其制备方法
CN103044314A (zh) * 2013-01-06 2013-04-17 先声药业有限公司 马来酸氨氯地平的制备方法
CN111689894A (zh) * 2019-03-13 2020-09-22 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平晶型
CN111689894B (zh) * 2019-03-13 2023-05-02 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平晶型
CN112110850A (zh) * 2019-06-20 2020-12-22 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平新晶型
CN112110850B (zh) * 2019-06-20 2023-05-02 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平新晶型
CN115974769A (zh) * 2022-11-29 2023-04-18 常州瑞明药业有限公司 一种马来酸左旋氨氯地平晶型及其制备方法和应用

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KR100843400B1 (ko) 2008-07-04

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