WO2008069469A1 - Anhydride de s-(-)-amlodipine camsylate cristalin et son procédé de préparation - Google Patents

Anhydride de s-(-)-amlodipine camsylate cristalin et son procédé de préparation Download PDF

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Publication number
WO2008069469A1
WO2008069469A1 PCT/KR2007/005718 KR2007005718W WO2008069469A1 WO 2008069469 A1 WO2008069469 A1 WO 2008069469A1 KR 2007005718 W KR2007005718 W KR 2007005718W WO 2008069469 A1 WO2008069469 A1 WO 2008069469A1
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WIPO (PCT)
Prior art keywords
amlodipine
anhydrate
crystalline
camsylate
camphorsulfonic acid
Prior art date
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PCT/KR2007/005718
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English (en)
Inventor
Dong Kwon Lim
Yong Sik Youn
Seog Beom Song
Il Hwan Cho
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Cj Corporation
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Publication of WO2008069469A1 publication Critical patent/WO2008069469A1/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 camsylate and a method of preparing the same.
  • 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methyl- 3,5-pyridinedicarboxylate is a long-acting calcium channel blocker useful in the treatment of cardiovascular diseases, such as angina pectoris, hypertension and 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 stereoisomer 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 (U. S. Pat. No.
  • the S-(-)-isomer of amlodipine is a potent calcium channel blocker.
  • amlodipine is administered in the form of S- (-)-amlodipine, substantially free of its R-(+)-amlodipine (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.
  • (-)-amlodipine salts or hydrates thereof and pharmaceutical compositions comprising the same examples include S-(-)-amlodipine benzenesulfonate 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: 1) 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.
  • S-(-)-amlodipine besylate which is in the form of 2.5 hydrate (water content: 7.5%).
  • 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.
  • 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 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 anhydrate of crystalline S-(-)-amlodipine camsylate, produced by the reaction of S- (-)-amlodipine with camphorsulfonic acid which is non-hygroscopic, non-corrosive and easy to manage.
  • An anhydrate of crystalline S-(-)-amlodipine camsylate exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, 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 camsylate, represented by the following Chemical
  • the anhydrate of crystalline S-(-)-amlodipine camsylate in accordance with the present invention includes an anhydrate of crystalline S-(-)-amlodipine (lR)-(-)-10-camsylate and an anhydrate of crystalline S-(-)-amlodipine (lS)-(+)-10-camsylate, has X-ray diffraction peaks at diffraction angles of 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° and 26.44°, and has a melting point of 94-99 0 C.
  • the anhydrate of crystalline S-(-)-amlodipine camsylate in accordance with the present invention has an equivalent or higher level of non- hygroscopicity and stability, and exhibits an equivalent or high level of solubility at pH 1.2-6.8.
  • the anhydrate of crystalline S-(-)-amlodipine camsylate 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 0 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.
  • the compound of the present invention has an equivalent to or higher solubility than that of S-(-)-amlodipine besylate 2.5 hydrate.
  • the present invention provides a method for preparing an anhydrate of crystalline S-(-)-amlodipine camsylate.
  • the preparation method according to the present invention features a reaction between S-(-)-amlodipine and camphorsulfonic acid in an inert organic solvent or distilled water (H O) to afford an anhydrate of crystalline S-(-)-amlodipine camsylate.
  • Camphorsulfonic acid the material for the compound of the present invention, is currently widely used for drugs and medicines and is a stable colorless solid that is neither hygroscopic nor caustic.
  • camphorsulfonic 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. Since the camphorsulfonic acid includes optical isomers, such as (lR)-(-)-10-camphorsulfonic acid and (lS)-(+)-10-camphorsulfonic acid, they are used as the camphorsulfonic acid.
  • the S-(-)-amlodipine camsylate according to the present invention refers to a compound obtained through a reaction of S-(-)-amlodipine and any one of the (lR)-(-)-10-camphorsulfonic acid and (lS)-(+)-10-camphorsulfonic acid.
  • Examples of the inert organic solvent suitable for the preparation method of the present invention include acetone, ethyl acetate, methanol, ethanol, isopropanol, ace- tonitrile, hexane, isopropyl ether, t-butyl methyl ether, and mixtures thereof.
  • S-(-)-amlodipine camsylate prepared using distilled water as a reaction solvent, is anhydrous and non-hygroscopic, unlike the fact known through the prior art.
  • the inert organic solvent or distilled water is used in a volumetric amount (ml) 5-50 times the weight (g) of the S-(-)-amlodipine used, and preferably in a volumetric amount (ml) 8-16 times the weight (g) of the S-(-)-amlodipine used.
  • To this solvent is added (lR)-(-)-10-camphorsulfonic acid or (lS)-(+)-10-camphorsulfonic acid in an amount of 1-2 equivalents, and preferably 1.02-1.2 equivalents per equivalent of S- (-)-amlodipine.
  • the anhydrate of crystalline S-(-)-amlodipine camsylate can be produced at a yield of 80% or higher.
  • the anhydrate of crystalline S-(-)-amlodipine camsylate produced by the method of the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, stability, photostability, formulation processability 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 camsylate 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 dispersing agent, 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, administration route and method, excretion rate, severity of illness, and the like.
  • the anhydrate of crystalline S-(-)-amlodipine camsylate may be administered in a single dose or in several doses per day with a daily dose ranging from 0.1 to 100 mg/kg, and preferably from 2.5 to 10 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.
  • 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 [89]
  • the anhydrates of crystalline S-(-)-amlodipine camsylate prepared in Examples 1 and 3, 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 EXAMPLE 3 Stability Test [106] [107] 1. Stability in Solid State [108] The anhydrate of crystalline S-(-)-amlodipine (lR)-(-)-10-camsylate prepared in Example 1, the anhydrate of S-(-)-amlodipine (lS)-(+)-10-camsylate prepared in Example 3 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 [126] [127] The anhydrate of crystalline S-(-)-amlodipine (lR)-(-)-10-camsylate prepared in Example 1, the anhydrate of crystalline S-(-)-amlodipine (lS)-(+)-10-camsylate prepared in Example 3 and the S-(-)-amlodipine besylate 2.5 hydrate prepared in Comparative Example 1 were stored for 4 weeks at 25 C in a photostability 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.
  • HPLC content
  • the anhydrate of crystalline S-(-)-amlodipine camsylate produced by the method of the present invention exhibits excellent physical and chemical properties including non-hygroscopicity, solubility, 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)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Dermatology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un anhydrate de S-(-)-amlodipine camsylate cristalin et son procédé de préparation. Cet anhydrate de s-(-)-amlodipine camsylate cristalin présente d'excellentes propriétés physiques et chimiques, notamment il présente une non-hygroscopicité, une bonne solubilité, une bonne stabilité, et une bonne photostabilité, il peut être stocké en toute sécurité sur le long terme et sa formulation présente une aptitude au traitement supérieure.
PCT/KR2007/005718 2006-12-04 2007-11-14 Anhydride de s-(-)-amlodipine camsylate cristalin et son procédé de préparation WO2008069469A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0121475 2006-12-04
KR1020060121475A KR100843401B1 (ko) 2006-12-04 2006-12-04 결정성 ｓ-(-)-암로디핀 캠실레이트 무수물 및 이의제조방법

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Cited By (3)

* 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
US9861638B2 (en) 2010-02-12 2018-01-09 Pfizer Inc. Salts and polymorphs of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
CN110372576A (zh) * 2019-07-10 2019-10-25 复旦大学 一种钙通道阻滞药物分子共晶体及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1343663A (zh) * 2000-09-15 2002-04-10 付俊昌 氨氯地平系列盐及其制备方法和用途
WO2002079158A1 (fr) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Nouvel amlodipine camsylate et son procede de preparation
WO2003043989A1 (fr) * 2001-11-22 2003-05-30 Xitian Zhang Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques
WO2004026834A1 (fr) * 2002-09-19 2004-04-01 Cj Corporation Sel acide organique cristallin d'amlodipine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1343663A (zh) * 2000-09-15 2002-04-10 付俊昌 氨氯地平系列盐及其制备方法和用途
WO2002079158A1 (fr) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Nouvel amlodipine camsylate et son procede de preparation
WO2003043989A1 (fr) * 2001-11-22 2003-05-30 Xitian Zhang Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques
WO2004026834A1 (fr) * 2002-09-19 2004-04-01 Cj Corporation Sel acide organique cristallin d'amlodipine

Cited By (6)

* 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
US9861638B2 (en) 2010-02-12 2018-01-09 Pfizer Inc. Salts and polymorphs of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
US10278974B2 (en) 2010-02-12 2019-05-07 Pfizer Inc. Salts and polymorphs of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one
CN110372576A (zh) * 2019-07-10 2019-10-25 复旦大学 一种钙通道阻滞药物分子共晶体及其制备方法

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KR100843401B1 (ko) 2008-07-04
KR20080050777A (ko) 2008-06-10

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