WO2009075504A2 - Forme cristalline du p-toluènesulfonate de bépostatine, son procédé de préparation et composition pharmaceutique la contenant - Google Patents

Forme cristalline du p-toluènesulfonate de bépostatine, son procédé de préparation et composition pharmaceutique la contenant Download PDF

Info

Publication number
WO2009075504A2
WO2009075504A2 PCT/KR2008/007266 KR2008007266W WO2009075504A2 WO 2009075504 A2 WO2009075504 A2 WO 2009075504A2 KR 2008007266 W KR2008007266 W KR 2008007266W WO 2009075504 A2 WO2009075504 A2 WO 2009075504A2
Authority
WO
WIPO (PCT)
Prior art keywords
bepotastine
toluenesulfonate
crystalline form
pharmaceutical composition
anhydrate
Prior art date
Application number
PCT/KR2008/007266
Other languages
English (en)
Other versions
WO2009075504A3 (fr
Inventor
Tae Hee Ha
Chang Hee Park
Jong Ouk Baek
Yong Hoon An
Han Kyong Kim
Kwee Hyun Suh
Original Assignee
Hanmi Pharm. Co., Ltd.
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 Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Publication of WO2009075504A2 publication Critical patent/WO2009075504A2/fr
Publication of WO2009075504A3 publication Critical patent/WO2009075504A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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 a crystalline form of (5)-4-[4-[(4- chloiOphenyl)-2-pyridylmethoxy]piperidin- 1 -yl]butyric acid(bepotastine) p- toluenesulfonate, a method for preparing same, and an anti-histaminic or antiallergic pharmaceutical composition comprising same.
  • the active ingredient of a pharmaceutical composition is required to be stable, maintaining its purity over a long period of storage, especially, when the active medicament is an optical isomer. Such physicochemical stability of an active ingredient can be best maintained when the active ingredient is of a non- hygroscopic crystalline form.
  • Bepotastine of formula (II) is a selective antihistaminic agent which exhibits rapid therapeutic effect while minimizing side effects such as sleepiness and arrhythmia.
  • Japanese Patent Publication No. Hei 2-25465 has disclosed such effects of bepotastine in the form of a racemic compound and pharmaceutically acceptable salts thereof:
  • Japanese Patent Publication No. 2000-198784 has also disclosed acid- addition salts of bepotastine prepared by adding pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, mandelic acid, succinic acid, tartaric acid, hibenzic acid, fendizoic acid, lactic acid and malic acid.
  • pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, mandelic acid, succinic acid, tartaric acid, hibenzic acid, fendizoic acid, lactic acid and malic acid.
  • most of the above conventional acid-addition salts of bepotastine are formulated in the form of an emulsion, syrup or hygroscopic crystal form.
  • Japanese Patent Publication No. 2000-198784 teaches that bepotastine benzenesulfonate and bepotastine benzonate are relatively stable and non-hygroscopic, and an antihistaminic drug containing bepotastine bezenesulfonate as an active ingredient (trade mark: Talion) is currently marketed by Tanabe in Japan.
  • an antihistaminic drug containing bepotastine bezenesulfonate as an active ingredient (trade mark: Talion) is currently marketed by Tanabe in Japan.
  • the stability of bepotastine benzenesulfonate has been reported to be unsatisfactory.
  • a stability study of bepotastine benzenesulfonate under a high temperature/humidity condition 40 ° C, 75% relative humidity
  • Japanese Patent Publication No. 2001-261553 has reported that unwanted racemization of bepotastine S-isomer occurs due to the presence of moisture during the formulation process of
  • the present inventors have endeavored to meet the above need, and have developed a crystalline form of bepotastine p-toluenesulfonate, which is non-hygroscopic and stable under a high temperature/humidity condition.
  • a crystalline form of bepotastine p-toluenesulfonate which is stable and non- hygroscopic under various conditions; a method for preparing said compound; and an anti-histaminic or anti-allergic pharmaceutical composition comprising said compound as an active ingredient.
  • X is 0 or 2.
  • Fig. 1 an X-ray powder diffraction (XRPD) spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate;
  • Fig. 2 a differential scanning calorimeter (DSC) scan of the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate;
  • Fig. 3 an XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate dihydrate
  • Fig. 4 a DSC scan of the inventive crystalline form of bepotastine p- toluenesulfonate dihydrate
  • Both of the crystalline forms of bepotastine p-toluenesulfonate of formula (I) can be identified by X-ray powder diffraction (XRPD) analysis, and each crystal form of the inventive crystalline bepotastine p-toluenesulfonate can be identified by determining the characteristic 2 theta (2 ⁇ ) diffraction angle peaks, relative peak intensities at the diffraction angles (p), and the distances between crystal facets (d), which can be determined by analyzing an XRPD spectrum obtained using CuK ⁇ radiation.
  • XRPD X-ray powder diffraction
  • each of the inventive crystalline forms of bepotastine p-toluenesulfonate can be identified by detecting the presence of a dehydration point in differential scanning calorimeter (DSC) scans, while the number of crystal water molecules can be detemiined by thermogravity analysis at the dehydration point, or by Karl-Fischer method.
  • the structure of the inventive salt compared of one molecule of bepotastine and one molecule of p- toluenesulfonic acid can be confirmed by 1 H nuclear magnetic resonance ( 1 H- NMR) spectrum analysis.
  • the XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate shows major peaks having relative peak intensity (1/I 0 ; I : the peak intensity; I 0 : the peak intensity of the maximum peak) of at least 50% at diffraction angles (2 ⁇ 0.2) of 17.9, 18.3, 21.5 and 21.9.
  • the XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate (Fig. 1) shows major peaks having relative peak intensity (1/I 0 ; I : the peak intensity; I 0 : the peak intensity of the maximum peak) of at least 50% at diffraction angles (2 ⁇ 0.2) of 17.9, 18.3, 21.5 and 21.9.
  • the XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate shows major peaks having relative peak intensity (1/I 0 ; I : the peak intensity; I 0
  • the XRPD spectrum of the inventive crystalline form of bepotastine p- toluenesulfonate dihydrate shows major peaks having relative peak intensity (1/I 0 ; I : the peak intensity; Io: the peak intensity of the maximum peak) of at least 50% at diffraction angles (2 ⁇ 0.2) of 14.6, 19.1, 20.2, 21.0, 21.9, 23.4, 24.5 and 25.2.
  • the XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate dihydrate (Fig. 3) shows major peaks having relative peak intensity (1/I 0 ; I : the peak intensity; Io: the peak intensity of the maximum peak) of at least 50% at diffraction angles (2 ⁇ 0.2) of 14.6, 19.1, 20.2, 21.0, 21.9, 23.4, 24.5 and 25.2.
  • the XRPD spectrum of the inventive crystalline form of bepotastine p-toluenesulfonate dihydrate Fig.
  • the present invention further provides methods of preparing the inventive crystalline forms of bepotastine p-toluenesulfonate.
  • the inventive crystalline form of bepotastine p-toluenesulfonate anhydrate may be prepared by a method which comprises the steps of treating bepotastine with p-toluenesulfonic acid in a molar ratio of 1 :0.9 to 1:1.2 in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, tetrahydrofuran and a mixture thereof; and optionally, recrystallizing bepotastine p-toluenesulfonate thus obtained from the above organic solvent.
  • the inventive crystalline form of bepotastine p-toluenesulfonate dihydrate may be prepared by a method which comprises the step of recrystallizing the crystalline form of bepotastine p-toluenesulfonate anhydrate from a mixture of water and an organic solvent selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile, acetone and a mixture thereof.
  • the S-isomer of bepotastine used in the inventive methods for preparing the crystalline forms of bepotastine p- toluenesulfonate may be prepared by the method described in U.S. Patent No. 6,307,052 or others.
  • the crystalline form of bepotastine p-toluenesulfonate of formula (I) prepared by the inventive method possesses a high optical purity of 99.5% or more and exhibits non-hygroscopic property and outstanding optical stability as compared to conventional crystal forms of bepotastine benzenesulfonate. Therefore, a pharmaceutical composition containing said compound can maintain a high optical purity under various conditions, e.g., a high temperature/humidity and a long term storage, and circulation condition.
  • an anti-histaminic or anti-allergic pharmaceutical composition comprising the crystalline form of bepotastine p-toluenesulfonate of formula (I) as an active ingredient and pharmaceutically acceptable carriers.
  • the anti-histaminic or anti-allergic pharmaceutical composition of the present invention may be advantageously used for preventing and treating histaminic or allergic diseases such as allergic rhinitis, urticaria, pruritus, nasal obstruction, dermatitis, and eczema.
  • the inventive composition for oral administration may be prepared by mixing the inventive crystalline form of bepotastine p-toluenesulfonate with pharmaceutically acceptable carriers, diluents or excipients, and representative examples of the pharmaceutically acceptable carriers, diluents or excipients may include excipients, e.g., starch, sugar and mannitol; fillers and extenders, e.g., calcium phosphate and silicic acid derivatives; binding agents, e.g., cellulose derivatives such as carboxy methyl cellulose and hydroxy propyl cellulose, gelatine, alginate, and polyvinyl pyrrolidone; lubricants, e.g., talc, calcium or magnesium stearate, hydrogenated castor oil and solid polyethylene glycol; disintegrants, e.g., povidone, croscarmellose sodium and crospovidone; and surfactants, e.g., polysolvate, cetylal
  • the inventive anhydrate and dihydrate crystalline forms of bepotastine p-toluenesulfonate showed minimized water-content increases as compared with the conventional compound, i.e., bepotastine benzenesulfonate anhydrate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur une forme cristalline optiquement stable et non hygroscopique du p-toluènesulfonate de l'acide (S)-4-[4-[(4-chlorophényl)-2-pyridylméthoxy]pipéridin-1-yl]butyrique (bépotastine) ; sur un procédé de préparation dudit composé ; et sur une composition pharmaceutique antihistaminique ou antiallergique comprenant ledit composé.
PCT/KR2008/007266 2007-12-12 2008-12-09 Forme cristalline du p-toluènesulfonate de bépostatine, son procédé de préparation et composition pharmaceutique la contenant WO2009075504A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070129014A KR20090061972A (ko) 2007-12-12 2007-12-12 베포타스틴 ｐ-톨루엔술폰산염의 결정형, 이의 제조방법 및이를 포함하는 약학 조성물
KR10-2007-0129014 2007-12-12

Publications (2)

Publication Number Publication Date
WO2009075504A2 true WO2009075504A2 (fr) 2009-06-18
WO2009075504A3 WO2009075504A3 (fr) 2009-08-27

Family

ID=40755973

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/007266 WO2009075504A2 (fr) 2007-12-12 2008-12-09 Forme cristalline du p-toluènesulfonate de bépostatine, son procédé de préparation et composition pharmaceutique la contenant

Country Status (2)

Country Link
KR (1) KR20090061972A (fr)
WO (1) WO2009075504A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011195500A (ja) * 2010-03-19 2011-10-06 Tokuyama Corp （ｓ）−４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸一ベンゼンスルホン酸塩の製造方法
WO2012048059A3 (fr) * 2010-10-06 2012-05-31 Ista Pharmaceuticals, Inc. Compositions de bépotastine
WO2012094283A2 (fr) 2011-01-04 2012-07-12 Ista Pharmaceuticals, Inc. Compositions de bépostatine
CN105092751A (zh) * 2014-05-15 2015-11-25 重庆华邦制药有限公司 分离和测定苯磺贝他斯汀光学异构体杂质的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101476508B1 (ko) * 2012-11-30 2014-12-26 씨제이헬스케어 주식회사 (S)-베포타스틴 p-톨루엔술폰산염의 신규 결정형 및 이의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000198784A (ja) * 1996-12-26 2000-07-18 Ube Ind Ltd 光学活性ピペリジン誘導体の酸付加塩及びその製法
WO2003074055A1 (fr) * 2002-03-06 2003-09-12 Altana Pharma Ag Composition pharmaceutique contenant un inhibiteur de la pde4 ou un inhibiteur de la pde3/4 et un antagoniste des recepteurs histaminiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000198784A (ja) * 1996-12-26 2000-07-18 Ube Ind Ltd 光学活性ピペリジン誘導体の酸付加塩及びその製法
WO2003074055A1 (fr) * 2002-03-06 2003-09-12 Altana Pharma Ag Composition pharmaceutique contenant un inhibiteur de la pde4 ou un inhibiteur de la pde3/4 et un antagoniste des recepteurs histaminiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KATO, MASAYA ET AL.: 'Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent bepotastine besilate' ARZNEIMITTEL-FORSCHUNG vol. 47, no. 10, 1997, pages 1116 - 1124 *
MORIYASU, SAIKO ET AL.: 'Involvement of histamine released from mast cells in acute radiation dermatitis in mice' JOURNAL OF PHARMACOLOGICAL SCIENCE vol. 104, no. 2, June 2007, pages 187 - 190 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011195500A (ja) * 2010-03-19 2011-10-06 Tokuyama Corp （ｓ）−４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸一ベンゼンスルホン酸塩の製造方法
WO2012048059A3 (fr) * 2010-10-06 2012-05-31 Ista Pharmaceuticals, Inc. Compositions de bépotastine
WO2012094283A2 (fr) 2011-01-04 2012-07-12 Ista Pharmaceuticals, Inc. Compositions de bépostatine
US10736841B2 (en) 2011-01-04 2020-08-11 Bausch & Lomb Incorporated Bepotastine compositions
CN105092751A (zh) * 2014-05-15 2015-11-25 重庆华邦制药有限公司 分离和测定苯磺贝他斯汀光学异构体杂质的方法

Also Published As

Publication number Publication date
WO2009075504A3 (fr) 2009-08-27
KR20090061972A (ko) 2009-06-17

Similar Documents

Publication Publication Date Title
EP2112155B1 (fr) Sel hydrogénosulfate de 2-acétoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine et sa préparation
AU2014239995B2 (en) Salt of omecamtiv mecarbil and process for preparing salt
JP5909185B2 (ja) 置換テトラゾール−１−イルフェノキシメチルチアゾール−２−イルピペリジニルピリミジン塩
US20230109556A1 (en) Compositions of essentially pure form iv of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
EP1853232B1 (fr) Forme cristalline stable de bifeprunox mesylate, formes posologiques et methodes d'utilisation
WO2017016463A1 (fr) Inhibiteur de l'egfr et sel pharmaceutiquement acceptable et polymorphe de celui-ci, et utilisation associée
EP2343296A1 (fr) Procédé pour la purification de la palipéridone
EP3428159A1 (fr) Formes cristallines de sel de mésylate de dérivé de pyridinyl-aminopyrimidine, procédés de préparation et applications associés
WO2009075504A2 (fr) Forme cristalline du p-toluènesulfonate de bépostatine, son procédé de préparation et composition pharmaceutique la contenant
KR102442536B1 (ko) 리나글립틴 결정형 및 이의 제조방법
KR100878698B1 (ko) 결정형의 베포타스틴 금속염 수화물, 이의 제조방법 및이를 포함하는 약학 조성물
US20220002297A1 (en) Polymorphs of x842
US20230174546A1 (en) Crystalline form a of glp-1 receptor agonist and preparation method therefor
RU2193560C2 (ru) Новая соль
US8993602B2 (en) Benzoic acid salt of otamixaban
KR101557832B1 (ko) (ｒ)-3-플루오로페닐-3,4,5-트리플루오로벤질카르밤산 1-아자비시클로 [2.2.2]옥트-3-일 에스테르의 안정한 결정성 염
KR101476508B1 (ko) (S)-베포타스틴 p-톨루엔술폰산염의 신규 결정형 및 이의 제조방법
IL304974A (en) Preparations of mainly pure configuration IV of N-((R)-3,2-dihydroxypropoxy)-4,3-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and their uses
US8471032B2 (en) Benzimidazole compound in crystal form and salt thereof
KR101132949B1 (ko) 베포타스틴 살리실산염, 이의 제조방법 및 이를 유효성분으로 포함하는 항히스타민 또는 항알레르기용 약학적 조성물
EP2649996A1 (fr) Formes cristallines de sartans de type Telmisartan avec des bêta-bloquants
WO2022048620A1 (fr) Polymorphes de formes cristallines de 3, 10-diméthoxy-5, 8, 13, 13a-tétrahydro-6h-isoquinolino [3, 2-a] isoquinolin-9-yl 3-fluorobenzènesulfonate et leurs sels
KR101307712B1 (ko) 결정형의 베포타스틴 금속염 수화물, 이의 제조방법 및 이를 포함하는 약학 조성물
WO2011027988A2 (fr) Nouvelle forme polymorphe de l'hydrogénosulfate de prasugrel
CN112759546B (zh) 3-(二甲氨基甲基)哌啶-4-醇衍生物及其制备方法和药物用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08858390

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08858390

Country of ref document: EP

Kind code of ref document: A2