WO2000014099A1 - Method of preparing form ii crystals of clarithromycin - Google Patents

Method of preparing form ii crystals of clarithromycin Download PDF

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Publication number
WO2000014099A1
WO2000014099A1 PCT/KR1999/000530 KR9900530W WO0014099A1 WO 2000014099 A1 WO2000014099 A1 WO 2000014099A1 KR 9900530 W KR9900530 W KR 9900530W WO 0014099 A1 WO0014099 A1 WO 0014099A1
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WIPO (PCT)
Prior art keywords
clarithromycin
water
crystals
organic solvent
immiscible organic
Prior art date
Application number
PCT/KR1999/000530
Other languages
French (fr)
Inventor
Tae Suk Lee
Ju Cheol Lee
Kyoung Ik Lee
Gwan Sun Lee
Wan Joo Kim
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.
Priority to DE69905176T priority Critical patent/DE69905176T2/en
Priority to US09/786,636 priority patent/US6506886B1/en
Priority to AT99941861T priority patent/ATE231879T1/en
Priority to EP99941861A priority patent/EP1112280B1/en
Priority to JP2000568857A priority patent/JP3779155B2/en
Publication of WO2000014099A1 publication Critical patent/WO2000014099A1/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water to provide said crystals having no residual organic solvent .
  • Clarithromycin 6-O-methylerythromycin A
  • Clarithromycin 6-O-methylerythromycin A
  • Crystal forms can be identified by infrared spectroscopy, differential scanning calorimetry and powder x-ray diffraction spectrophotometry .
  • Form I crystals of clarithromycin are prepared by recrystallization from ethanol, tetrahydrofuran, isopropyl acetate, isopropyl alcohol or a mixture thereof.
  • the thermodynamically more stable Form II is used in the drug formulations currently on the market.
  • Form II crystals of clarithromycin have been prepared by crystallization from chloroform/isopropyl ether (1:2)
  • Form II crystals may be obtained by heating Form I crystals under a vacuum at 80°C or higher for a prolonged time (see International Publication No. WO 98/04573), but this method has the problem of low productivity.
  • a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water or with a mixture of water and a water-immiscible organic solvent .
  • Fig. 1 shows the powder X-ray diffraction spectrum of clarithromycin crystal Form II. DETAILED DESCRIPTION OF THE INVENTION
  • the method of preparing Form II crystals of clarithromycin in accordance with the present invention comprises the step of treating clarithromycin with water or with a mixture of water and a water-immiscible organic solvent and isolating treated crystals.
  • clarithromycin refers to refined crystal Form I or mixtures of refined crystal Form I and Form II, or crude reaction product formed during the process of the preparation thereof. Representative methods of preparing clarithromycin are described in U.S. Patent Nos. 4,331,803, 4,670,549, 4,672,109 and 4,990,602, and European Patent No. 260 938.
  • the treating step in accordance with the present invention may be performed at an ambient temperature with stirring for a period sufficient to convert Form I crystals to Form II crystals of clarithromycin, e.g., about 1 to 4 hours . Water which may be distilled or deionized water is used in the inventive process in an amount ranging from 3 to 10 times that of clarithromycin used.
  • the water-immiscible organic solvents optionally used in the present invention are those which do not dissolve clarithromycin to any significant extent, and examples thereof include C hydrocarbons, diethyl ether, ethyl acetate, methyl acetate and the like.
  • the optional water- immiscible organic solvent functions to dissolve impurities that may be present in a clarithromycin feed, thereby further increasing the purity of the product.
  • the organic solvent may be employed in an amount ranging from 0.5 to 2 times that of clarithromycin used.
  • the resultant crystals are filtered and dried in a conventional manner to give pure clarithromycin crystal Form II in a high yield of at least 95%.
  • the method of the present invention is very simple and provides pure Form II crystals of clarithromycin having no residual organic solvent in a high yield of greater than 95% at a low process cost.
  • Example 1 Recovering of Form II crystals of clarithromycin from Water lOOg of clarithromycin (purity: 95.5%) was added to 500ml of water and the resulting mixture was stirred vigorously at room temperature for 2 hours. The crystals were filtered and dried overnight in a vacuum oven of 60 °C to give 97g of clarithromycin crystal Form II (purity: 97.4%, yield: 97%) .
  • Example 2 Recovering of Form II crystals of clarithromycin from Water and Hexane lOOg of clarithromycin (purity: 95.5%) was added to 500ml of water and the resulting mixture was stirred vigorously at room temperature for 2 hours. 100ml of hexane was added thereto, and the mixture was further stirred at room temperature for 1 hour. The resulting crystals were filtered and dried overnight in a vacuum oven of 60°C to give 95g of clarithromycin crystal Form II (purity: 97.7%, yield: 95%) .
  • Example 3 Recovering of Form II crystals of clarithromycin from Water and Ethyl acetate
  • Example 2 The procedure of Example 2 was repeated except that ethyl acetate was used instead of hexane, to give 95g of clarithromycin crystal Form II (purity: 98.0%, yield: 95%) .
  • Example 4 Recovering of Form II crystals of clarithromycin from Water and Methyl acetate The procedure of Example 2 was repeated except that methyl acetate was used instead of hexane, to give 95g of clarithromycin crystal Form II (purity: 97.9%, yield: 95%).
  • Example 5 Recovering of Form II crystals of clarithromycin from Water and Diethyl Ether
  • Example 2 The procedure of Example 2 was repeated except that diethyl ether was used instead of hexane, to give 97g of clarithromycin crystal Form II (purity: 97.5%, yield: 97%).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Form II crystals of clarithromycin can be easily prepared by treating clarithromycin of different crystal forms with water or with a mixture of water and a water-immiscible organic solvent and isolating treated crystals by filtration.

Description

METHOD OF PREPARING FORM II CRYSTALS OF CLARITHROMYCIN
FIELD OF THE INVENTION
The present invention relates to a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water to provide said crystals having no residual organic solvent .
BACKGROUND OF THE INVENTION
Clarithromycin, 6-O-methylerythromycin A, is a semisynthetic macrolide antibiotic of formula (I) which exhibits a wide range of antibacterial activity:
Figure imgf000003_0001
It has been discovered that clarithromycin exists in two distinct crystalline forms, "Form I" and "Form II", as described in International Publication Nos. WO 98/04573 and
WO 98/04574. The crystal forms can be identified by infrared spectroscopy, differential scanning calorimetry and powder x-ray diffraction spectrophotometry . Form I crystals of clarithromycin are prepared by recrystallization from ethanol, tetrahydrofuran, isopropyl acetate, isopropyl alcohol or a mixture thereof. However, the thermodynamically more stable Form II is used in the drug formulations currently on the market. Form II crystals of clarithromycin have been prepared by crystallization from chloroform/isopropyl ether (1:2)
(see Merck Index 12th ed., pp. 395), but this method has a problem in that the resulting Form II crystals contain residual organic solvents. Alternatively, Form II crystals may be obtained by heating Form I crystals under a vacuum at 80°C or higher for a prolonged time (see International Publication No. WO 98/04573), but this method has the problem of low productivity.
International Publication No. WO 98/04574 teaches a method of preparing clarithromycin crystal Form II using various organic solvent systems or aqueous solvents containing water-miscible organic solvents. However, this method is hampered by a relatively low yield (approximately 9 to 83%) and still has the problem of entrained organic solvents .
Accordingly, there has existed a need to develop a new simple method for preparing pure Form II crystals of clarithromycin in a high yield.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide pure Form II crystals of clarithromycin having no residual solvent in a high yield.
In accordance with the present invention, there is provided a method of preparing Form II crystals of clarithromycin comprising treating clarithromycin with water or with a mixture of water and a water-immiscible organic solvent .
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and features of the present invention will become apparent from the following description, when taken in conjunction with the accompanying drawing wherein:
Fig. 1 shows the powder X-ray diffraction spectrum of clarithromycin crystal Form II. DETAILED DESCRIPTION OF THE INVENTION
The method of preparing Form II crystals of clarithromycin in accordance with the present invention comprises the step of treating clarithromycin with water or with a mixture of water and a water-immiscible organic solvent and isolating treated crystals.
The term "clarithromycin" as used herein refers to refined crystal Form I or mixtures of refined crystal Form I and Form II, or crude reaction product formed during the process of the preparation thereof. Representative methods of preparing clarithromycin are described in U.S. Patent Nos. 4,331,803, 4,670,549, 4,672,109 and 4,990,602, and European Patent No. 260 938. The treating step in accordance with the present invention may be performed at an ambient temperature with stirring for a period sufficient to convert Form I crystals to Form II crystals of clarithromycin, e.g., about 1 to 4 hours . Water which may be distilled or deionized water is used in the inventive process in an amount ranging from 3 to 10 times that of clarithromycin used.
The water-immiscible organic solvents optionally used in the present invention are those which do not dissolve clarithromycin to any significant extent, and examples thereof include C hydrocarbons, diethyl ether, ethyl acetate, methyl acetate and the like. The optional water- immiscible organic solvent functions to dissolve impurities that may be present in a clarithromycin feed, thereby further increasing the purity of the product. The organic solvent may be employed in an amount ranging from 0.5 to 2 times that of clarithromycin used.
After the clarithromycin crystals are sufficiently treated, the resultant crystals are filtered and dried in a conventional manner to give pure clarithromycin crystal Form II in a high yield of at least 95%.
The method of the present invention is very simple and provides pure Form II crystals of clarithromycin having no residual organic solvent in a high yield of greater than 95% at a low process cost.
The following Examples are intended to further illustrate the present invention without limiting its scope.
Example 1 : Recovering of Form II crystals of clarithromycin from Water lOOg of clarithromycin (purity: 95.5%) was added to 500ml of water and the resulting mixture was stirred vigorously at room temperature for 2 hours. The crystals were filtered and dried overnight in a vacuum oven of 60 °C to give 97g of clarithromycin crystal Form II (purity: 97.4%, yield: 97%) .
Example 2 : Recovering of Form II crystals of clarithromycin from Water and Hexane lOOg of clarithromycin (purity: 95.5%) was added to 500ml of water and the resulting mixture was stirred vigorously at room temperature for 2 hours. 100ml of hexane was added thereto, and the mixture was further stirred at room temperature for 1 hour. The resulting crystals were filtered and dried overnight in a vacuum oven of 60°C to give 95g of clarithromycin crystal Form II (purity: 97.7%, yield: 95%) .
Example 3 : Recovering of Form II crystals of clarithromycin from Water and Ethyl acetate
The procedure of Example 2 was repeated except that ethyl acetate was used instead of hexane, to give 95g of clarithromycin crystal Form II (purity: 98.0%, yield: 95%) .
Example 4 : Recovering of Form II crystals of clarithromycin from Water and Methyl acetate The procedure of Example 2 was repeated except that methyl acetate was used instead of hexane, to give 95g of clarithromycin crystal Form II (purity: 97.9%, yield: 95%). Example 5 : Recovering of Form II crystals of clarithromycin from Water and Diethyl Ether
The procedure of Example 2 was repeated except that diethyl ether was used instead of hexane, to give 97g of clarithromycin crystal Form II (purity: 97.5%, yield: 97%).
The powder X-ray diffraction pattern of each clarithromycin obtained in Examples 1 to 5 was identical to that of clarithromycin crystal Form II shown in Figure 1. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

What is claimed is:
1. A method of preparing Form II crystals of clarithromycin comprising treating a clarithromycin feed with water or with a mixture of water and a water-immiscible organic solvent and isolating treated crystals by filtration.
2. The method of claim 1, wherein the water- immiscible organic solvent is selected from the group consisting of a C hydrocarbon, diethyl ether, ethyl acetate and methyl acetate.
3. The method of claim 1 or 2 , wherein the water- immiscible organic solvent is hexane.
4. The method of claim 1, wherein water is used in an amount ranging from 3 to 10 times that of the clarithromycin feed.
5. The method of claim 1, wherein the water- immiscible organic solvent is used in an amount ranging from 0.5 to 2 times that of the clarithromycin feed.
PCT/KR1999/000530 1998-09-09 1999-09-08 Method of preparing form ii crystals of clarithromycin WO2000014099A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE69905176T DE69905176T2 (en) 1998-09-09 1999-09-08 METHOD FOR PRODUCING CLARITHROMYCINE CRYSTALS OF FORM II
US09/786,636 US6506886B1 (en) 1998-09-09 1999-09-08 Method of preparing form II crystals of clarithromycin
AT99941861T ATE231879T1 (en) 1998-09-09 1999-09-08 METHOD FOR PRODUCING CLARITHROMYCIN CRYSTALS OF FORM II
EP99941861A EP1112280B1 (en) 1998-09-09 1999-09-08 Method of preparing form ii crystals of clarithromycin
JP2000568857A JP3779155B2 (en) 1998-09-09 1999-09-08 Method for producing clarithromycin crystal form II

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1998/37181 1998-09-09
KR10-1998-0037181A KR100377159B1 (en) 1998-09-09 1998-09-09 Method for preparing Form 2 of clarithromycin without residual solvent

Publications (1)

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WO2000014099A1 true WO2000014099A1 (en) 2000-03-16

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US (1) US6506886B1 (en)
EP (1) EP1112280B1 (en)
JP (1) JP3779155B2 (en)
KR (1) KR100377159B1 (en)
AT (1) ATE231879T1 (en)
DE (1) DE69905176T2 (en)
ES (1) ES2192072T3 (en)
WO (1) WO2000014099A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094843A1 (en) * 2001-05-22 2002-11-28 Pfizer Products Inc. Crystal forms of azithromycin
US6599884B2 (en) 1999-12-16 2003-07-29 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin polymorphs and novel polymorph IV
KR100377159B1 (en) * 1998-09-09 2003-08-19 한미약품공업 주식회사 Method for preparing Form 2 of clarithromycin without residual solvent
US6617436B2 (en) 2000-02-29 2003-09-09 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
US6624292B2 (en) 2000-01-11 2003-09-23 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin polymorphs
US6861413B2 (en) 2001-05-22 2005-03-01 Pfizer Inc. Stable non-dihydrate azithromycin oral suspensions
USRE39087E1 (en) 1998-08-21 2006-05-02 Apotex, Inc. Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof
EP1652851A1 (en) * 2001-05-22 2006-05-03 Pfizer Products Inc. New crystal form of Azithromycin
CN103087130A (en) * 2013-02-06 2013-05-08 浙江国邦药业有限公司 Clarithromycin crystal form transformation method

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US6565882B2 (en) * 2000-02-24 2003-05-20 Advancis Pharmaceutical Corp Antibiotic composition with inhibitor
US6544555B2 (en) 2000-02-24 2003-04-08 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
US20020068078A1 (en) * 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof
US6541014B2 (en) * 2000-10-13 2003-04-01 Advancis Pharmaceutical Corp. Antiviral product, use and formulation thereof
US20020197314A1 (en) * 2001-02-23 2002-12-26 Rudnic Edward M. Anti-fungal composition
KR100408848B1 (en) * 2001-03-12 2003-12-06 주식회사 씨트리 Purification process of Clarithromycin
JP2006528190A (en) * 2003-07-21 2006-12-14 アドバンシス ファーマスーティカル コーポレイション Antibiotic preparations, their use and preparation
JP2006528185A (en) * 2003-07-21 2006-12-14 アドバンシス ファーマスーティカル コーポレイション Antibiotic preparations, their use and preparation
US8313776B2 (en) * 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
CA2535177A1 (en) * 2003-08-11 2005-02-24 Advancis Pharmaceutical Corporation Robust pellet
CA2535398C (en) * 2003-08-12 2013-11-12 Advancis Pharmaceuticals Corporation Antibiotic product, use and formulation thereof
AU2004270170B2 (en) * 2003-08-29 2011-01-27 Shionogi, Inc. Antibiotic product, use and formulation thereof
WO2005027877A1 (en) * 2003-09-15 2005-03-31 Advancis Pharmaceutical Corporation Antibiotic product, use and formulation thereof
CA2550983C (en) * 2003-12-24 2013-09-17 Advancis Pharmaceutical Corporation Enhanced absorption of modified release dosage forms
JP2008505124A (en) * 2004-07-02 2008-02-21 アドバンシス ファーマスーティカル コーポレイション Pulse delivery tablets
WO2007008537A2 (en) * 2005-07-07 2007-01-18 Elan Pharma International, Limited Nanoparticulate clarithromycin formulations
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication

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WO1998004574A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Preparation of crystal form ii of clarithromycin
WO1998004573A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Crystal form i of clarithromycin
WO1998031699A1 (en) * 1997-01-17 1998-07-23 Abbott Laboratories Crystal form 0 of clarithromycin

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US5187140A (en) * 1989-10-18 1993-02-16 Union Carbide Chemicals & Plastics Technology Corporation Alkylene oxide catalysts containing high silver content
US5844105A (en) * 1996-07-29 1998-12-01 Abbott Laboratories Preparation of crystal form II of clarithromycin
KR100377159B1 (en) * 1998-09-09 2003-08-19 한미약품공업 주식회사 Method for preparing Form 2 of clarithromycin without residual solvent

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1998004574A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Preparation of crystal form ii of clarithromycin
WO1998004573A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Crystal form i of clarithromycin
WO1998031699A1 (en) * 1997-01-17 1998-07-23 Abbott Laboratories Crystal form 0 of clarithromycin

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39087E1 (en) 1998-08-21 2006-05-02 Apotex, Inc. Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof
KR100377159B1 (en) * 1998-09-09 2003-08-19 한미약품공업 주식회사 Method for preparing Form 2 of clarithromycin without residual solvent
US6599884B2 (en) 1999-12-16 2003-07-29 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin polymorphs and novel polymorph IV
US6987175B2 (en) 2000-01-11 2006-01-17 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin polymorphs
US6624292B2 (en) 2000-01-11 2003-09-23 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin polymorphs
US6617436B2 (en) 2000-02-29 2003-09-09 Teva Pharmaceutical Industries Ltd. Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
US7101858B2 (en) 2000-02-29 2006-09-05 Teva Pharmaceutical Industries, Ltd. Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same
US7053192B2 (en) 2001-05-22 2006-05-30 Pfizer Inc. Crystal forms of azithromycin
US7105179B2 (en) 2001-05-22 2006-09-12 Pfizer Inc. Crystal forms of azithromycin
EP1652851A1 (en) * 2001-05-22 2006-05-03 Pfizer Products Inc. New crystal form of Azithromycin
WO2002094843A1 (en) * 2001-05-22 2002-11-28 Pfizer Products Inc. Crystal forms of azithromycin
EP1671979A1 (en) * 2001-05-22 2006-06-21 Pfizer Products Inc. New Cristal Form of Azithromycin
US7081525B2 (en) 2001-05-22 2006-07-25 Pfizer Inc. Crystal forms of azithromycin
US6861413B2 (en) 2001-05-22 2005-03-01 Pfizer Inc. Stable non-dihydrate azithromycin oral suspensions
US6977243B2 (en) 2001-05-22 2005-12-20 Pfizer Inc. Crystal forms of azithromycin
EA007618B1 (en) * 2001-05-22 2006-12-29 Пфайзер Продактс Инк. Crystalline sesquihydrate azithromycin, pharmaceutical composition and method for treatment based thereon
US7282486B2 (en) 2001-05-22 2007-10-16 Pfizer Inc Crystal forms of azithromycin
US7307156B2 (en) 2001-05-22 2007-12-11 Pfizer Inc. Crystal forms of azithromycin
US7309782B2 (en) 2001-05-22 2007-12-18 Pfizer Inc. Crystal forms of azithromycin
EA009611B1 (en) * 2001-05-22 2008-02-28 Пфайзер Продактс Инк. Crystal forms of azithromycin
CN103087130A (en) * 2013-02-06 2013-05-08 浙江国邦药业有限公司 Clarithromycin crystal form transformation method

Also Published As

Publication number Publication date
DE69905176D1 (en) 2003-03-06
KR100377159B1 (en) 2003-08-19
JP3779155B2 (en) 2006-05-24
ATE231879T1 (en) 2003-02-15
JP2002524465A (en) 2002-08-06
ES2192072T3 (en) 2003-09-16
EP1112280B1 (en) 2003-01-29
EP1112280A1 (en) 2001-07-04
US6506886B1 (en) 2003-01-14
DE69905176T2 (en) 2003-10-09
KR20000019206A (en) 2000-04-06

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