WO2008102161A2 - Crystalline minocycline base and processes for its preparation - Google Patents

Crystalline minocycline base and processes for its preparation Download PDF

Info

Publication number
WO2008102161A2
WO2008102161A2 PCT/GB2008/000625 GB2008000625W WO2008102161A2 WO 2008102161 A2 WO2008102161 A2 WO 2008102161A2 GB 2008000625 W GB2008000625 W GB 2008000625W WO 2008102161 A2 WO2008102161 A2 WO 2008102161A2
Authority
WO
WIPO (PCT)
Prior art keywords
minocycline
minocycline base
crystalline
base
organic solvent
Prior art date
Application number
PCT/GB2008/000625
Other languages
French (fr)
Other versions
WO2008102161A9 (en
WO2008102161A3 (en
Inventor
Zita Mendes
Jose Rafael Antunes
Susana Marto
William Heggie
Original Assignee
Hovione Inter 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
Priority to DK08709507.1T priority Critical patent/DK2125705T3/en
Priority to JP2009550320A priority patent/JP2010519247A/en
Priority to CA2722496A priority patent/CA2722496C/en
Priority to ES08709507.1T priority patent/ES2610434T3/en
Priority to NZ579626A priority patent/NZ579626A/en
Priority to BRPI0807319-8A priority patent/BRPI0807319B1/en
Priority to EP08709507.1A priority patent/EP2125705B1/en
Application filed by Hovione Inter Ltd. filed Critical Hovione Inter Ltd.
Priority to CN2008800059328A priority patent/CN101679218B/en
Priority to BR122021000846-9A priority patent/BR122021000846B1/en
Priority to AU2008217619A priority patent/AU2008217619B2/en
Priority to MX2009008980A priority patent/MX2009008980A/en
Priority to US12/528,209 priority patent/US8258327B2/en
Priority to RU2009135403/04A priority patent/RU2485095C2/en
Publication of WO2008102161A2 publication Critical patent/WO2008102161A2/en
Publication of WO2008102161A9 publication Critical patent/WO2008102161A9/en
Publication of WO2008102161A3 publication Critical patent/WO2008102161A3/en
Priority to IL200544A priority patent/IL200544A0/en
Priority to NO20092960A priority patent/NO20092960L/en
Priority to US13/599,116 priority patent/US9416097B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides crystalline minocycline base including three new polymorphic forms thereof, and also describes a process to obtain pure minocycline base in a crystalline form wherein all the impurities are controlled, especially the impurity 4-epi minocycline, to very low levels.
  • Minocycline is a member of the broad spectrum tetracycline antibiotics, which has a broader spectrum than the other members of this group of compounds.
  • Minocycline is widely used in therapy, primarily to treat acne and rosacea at a once daily dose of 100mg.
  • Minocycline may be used as base per se or as non-toxic acid addition salts of organic or inorganic acids, e.g. sulfonic, trichloroacetic or hydrochloric acid.
  • Minocycline base previously known before this invention only in the amorphous form, is not as stable as the corresponding acid addition salts and hence, methods to provide a stable form of minocycline base which makes its use promising as an active ingredient have been examined.
  • the present invention describes crystalline minocycline base, including new polymorphic forms of crystalline minocycline base and novel processes for their preparation.
  • the present inventors have now found that, surprisingly, minocycline base can in fact be provided in a stable crystalline form. They have also found three new polymorphic forms of crystalline minocycline base.
  • the invention provides crystalline minocycline base.
  • polymorphic Form I of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
  • Crystalline Form I of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.1 and an infrared spectrum of Fig.2.
  • Crystalline Form 1 is characterised by an X-ray diffraction pattern having peaks at 5.2, 7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8, 19.3, 19.5, 20.7, 21.3, 21.8, 22.3, 23.1 , 24.0, 25.3, 25.7 and 26.5 ⁇ 0.2° 2 ⁇ , as given in Fig.1. It is further characterised by an infrared spectrum having peaks at 1646,1602, 1581 , 1470, 1397, 1364, 1286, 1218, 1182, 1134, 1072, 1061 , 1023, 1001 , 969, 950, 874, 850, 716, 636, 620 and 545 ⁇ 4 cm "1 as given in Fig. 2.
  • the invention provides a process for the preparation of polymorphic Form I of crystalline minocycline base, which process comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallization from the mixture.
  • the process comprises suspending amorphous minocycline base in an organic solvent chosen from ethers, cooling the heterogeneous mixture to a temperature of from O 0 C tO 3O 0 C, the preferred range being from 10 0 C to 15 0 C and isolating Form I from the reaction mixture.
  • polymorphic Form Il of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
  • Crystalline Form Il of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.3 and an infrared spectrum of Fig.4.
  • Crystalline Form Il is characterised by an X-ray diffraction pattern having peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1 , 17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1 , 27.5, 28.0 and 29.1 ⁇ 0.2° 2 ⁇ , as given in Fig.3.
  • a process for the preparation of polymorphic Form Il of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from esters followed by crystallization from the mixture.
  • the process comprises suspending amorphous minocycline base in an organic solvent chosen from esters, cooling the heterogeneous mixture to a temperature of from O 0 C to 3O 0 C, the preferred range being from 10 0 C to 15 0 C and isolating the Form Il from the reaction mixture.
  • ester Any suitable ester may be used as solvent, but it is preferred to use ethyl acetate.
  • polymorphic Form III of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art. Crystalline Form III of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.5 and an infrared spectrum of Fig.6.
  • Crystalline Form III is characterised by an X-ray diffraction pattern having peaks at 6.5, 10.0, 13.2, 15.1 , 16.5, 17.9, 19.6, 20.2, 21.1 , 22.3, 23.7, 24.8, 26.4, 28.1 and 30.5 ⁇ 0.2° 2 ⁇ , as given in Fig. 5.
  • a process for the preparation of polymorphic Form III of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from alcohols followed by crystallization from the mixture.
  • the process comprises suspending amorphous minocycline base in an organic solvent chosen from alcohols, cooling the heterogeneous mixture to a temperature of from O 0 C to 3O 0 C, the preferred range being from 1O 0 C to 15 0 C and isolating the Form III from the reaction mixture.
  • Any suitable alcohol may be used a solvent, but it is preferred to use ethanol.
  • the crystalline minocycline bases in Forms I, Il and III obtained by the processes described above have a high purity with all the impurities controlled, especially 4-epi minocycline, which is typically below 1. 2% w/w (ie by weight of the base).
  • the invention provides crystalline minocycline base substantially free of 4-epi minocycline.
  • substantially free we mean that no more than about 1. 2% impurity by weight of the polymorph (w/w) is present.
  • the impurity level is less than 1. 2% w/w.
  • the invention provides crystalline minocycline base comprising less than 1.2% w/w (by weight of the base) of 4-epi minocycline.
  • Another aspect of the invention provides processes for preparing amorphous minocycline base on an industrial scale, wherein the minocycline base is obtained in high purity, especially maintaining low levels of the content of 4-epi-minocycline.
  • a process for preparing amorphous minocycline base comprises spray drying a solution or suspension of minocycline, in an organic solvent, preferably chosen from methyl tert-butyl ether, dichloromethane or isopropyl acetate
  • a preferred process for preparing amorphous minocycline base comprises:
  • Any suitable solvent may be used, and preferred solvents include methyl tert-butyl ether, dichloromethane or isopropyl acetate.
  • any suitable technique for the spray drying may be used.
  • conventional spray drying techniques as will be clear to those skilled in the art) may be employed.
  • EXAMPLE 1 Preparation of Form I of crystalline minocycline base Amorphous minocycline base (0.5g) is suspended in methyl tert-butyl ether (4ml) and the resulting heterogeneous mixture stirred for about 2 hours at a temperature between O 0 C and 3O 0 C, preferably between 1O 0 C and 15 0 C.
  • the product is filtered, washed with methyl tert-butyl ether (1 ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
  • Amorphous minocycline base (0.5g) is dissolved in methyl tert-butyl ether (6ml) and the resulting solution stirred at a temperature between O 0 C and 3O 0 C, preferably between 1O 0 C and 15 0 C.
  • EXAMPLE 3 Preparation of Form Il of crystalline minocycline base Amorphous minocycline base (2Og) is suspended in ethyl acetate (160ml) and the resulting heterogeneous mixture stirred for about 3 hours at a temperature between O 0 C and 3O 0 C, preferably between 1O 0 C and 15 0 C.
  • the product is filtered, washed with ethyl acetate (10ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
  • HPLC purity 99.5% in area 4-epi minocycline: 0.11% in area.
  • Amorphous minocycline base (5 g) is dissolved in ethyl acetate (40ml) and the resulting solution stirred for about 3 hours at a temperature between O 0 C and 3O 0 C, preferably between 1O 0 C and 15 0 C whereupon Form Il of crystalline minocycline base precipitated.
  • the product is filtered, washed with ethyl acetate (5ml) and dried under vacuum at about 45°C-50°C to yield Form Il of crystalline minocycline base.
  • Amorphous minocycline base (0.5g) is suspended in ethyl alcohol (2.5ml) and the resulting heterogeneous mixture stirred for at least 10 hours at a temperature between O 0 C and 3O 0 C preferably between 1O 0 C and 15 0 C.
  • the product is filtered, washed with ethyl alcohol (0.5ml) and dried under vacuum at about 45°C-50°C to yield Form III of crystalline minocycline base.
  • a solution of minocycline base in dichloromethane, isopropyl acetate or methyl tert- butyl ether was isolated by spray drying in conventional spray drying equipment using an inlet temperature between 45 0 C and 105 0 C, and an outlet temperature between 3O 0 C and 75 0 C.
  • the isolated product can be used directly to obtain any of the Forms of crystalline minocycline base or can be subjected to a post drying step under vacuum at about 45 0 C to yield pure amorphous minocycline base.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides crystalline minocycline base. In particular, three crystalline polymorphic forms, designated Form I, Form Il and Form III, of minocycline base are provided. These are characterised by XRD and IR data. Processes for preparing the new polymorphic forms are also provided. For example, Form I is prepared by dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallisation from the mixture.

Description

CRYSTALLINE MINOCYCLINE BASE AND PROCESSES FOR ITS PREPARATION
The present invention provides crystalline minocycline base including three new polymorphic forms thereof, and also describes a process to obtain pure minocycline base in a crystalline form wherein all the impurities are controlled, especially the impurity 4-epi minocycline, to very low levels.
Background of the Invention
Minocycline is a member of the broad spectrum tetracycline antibiotics, which has a broader spectrum than the other members of this group of compounds.
Minocycline is widely used in therapy, primarily to treat acne and rosacea at a once daily dose of 100mg.
The preparation of minocycline is disclosed in US 3 148 212; US 3 226 436 and US 4 849 136.
Minocycline may be used as base per se or as non-toxic acid addition salts of organic or inorganic acids, e.g. sulfonic, trichloroacetic or hydrochloric acid.
Minocycline base, previously known before this invention only in the amorphous form, is not as stable as the corresponding acid addition salts and hence, methods to provide a stable form of minocycline base which makes its use promising as an active ingredient have been examined.
Detailed Description
The present invention describes crystalline minocycline base, including new polymorphic forms of crystalline minocycline base and novel processes for their preparation. The present inventors have now found that, surprisingly, minocycline base can in fact be provided in a stable crystalline form. They have also found three new polymorphic forms of crystalline minocycline base.
Accordingly, in its broadest aspect, the invention provides crystalline minocycline base.
In one aspect, polymorphic Form I of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
Crystalline Form I of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.1 and an infrared spectrum of Fig.2.
Crystalline Form 1 is characterised by an X-ray diffraction pattern having peaks at 5.2, 7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8, 19.3, 19.5, 20.7, 21.3, 21.8, 22.3, 23.1 , 24.0, 25.3, 25.7 and 26.5 ± 0.2° 2Θ, as given in Fig.1. It is further characterised by an infrared spectrum having peaks at 1646,1602, 1581 , 1470, 1397, 1364, 1286, 1218, 1182, 1134, 1072, 1061 , 1023, 1001 , 969, 950, 874, 850, 716, 636, 620 and 545 ± 4 cm"1 as given in Fig. 2.
In another aspect, the invention provides a process for the preparation of polymorphic Form I of crystalline minocycline base, which process comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallization from the mixture.
Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from ethers, cooling the heterogeneous mixture to a temperature of from O0C tO 3O0C, the preferred range being from 100C to 150C and isolating Form I from the reaction mixture.
Any suitable ether solvent may be used, but is preferred to use methyl tert-butyl ether. In another aspect, polymorphic Form Il of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
Crystalline Form Il of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.3 and an infrared spectrum of Fig.4.
Crystalline Form Il is characterised by an X-ray diffraction pattern having peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1 , 17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1 , 27.5, 28.0 and 29.1 ± 0.2° 2Θ, as given in Fig.3. It is further characterised by an infrared spectrum having peaks at 1644, 1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287, 1251 , 1217, 1186, 1166, 1136, 1061 , 999, 970, 874, 716, 621 and 585 ± 4 cm"1, as given in Fig. 4.
In another aspect, a process for the preparation of polymorphic Form Il of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from esters followed by crystallization from the mixture.
Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from esters, cooling the heterogeneous mixture to a temperature of from O0C to 3O0C, the preferred range being from 100C to 150C and isolating the Form Il from the reaction mixture.
Any suitable ester may be used as solvent, but it is preferred to use ethyl acetate.
In another aspect, polymorphic Form III of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art. Crystalline Form III of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.5 and an infrared spectrum of Fig.6.
Crystalline Form III is characterised by an X-ray diffraction pattern having peaks at 6.5, 10.0, 13.2, 15.1 , 16.5, 17.9, 19.6, 20.2, 21.1 , 22.3, 23.7, 24.8, 26.4, 28.1 and 30.5 ± 0.2° 2Θ, as given in Fig. 5. It is further characterised by an infrared spectrum having peaks at 1647, 1605, 1581 , 1470, 1399, 1307, 1286, 1251 , 1216, 1195, 1179, 1136, 1094, 1058, 1024, 1000, 973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515, 496 and 413 ± 4 cm"1, as given in Fig. 6.
In another aspect, a process for the preparation of polymorphic Form III of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from alcohols followed by crystallization from the mixture.
Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from alcohols, cooling the heterogeneous mixture to a temperature of from O0C to 3O0C, the preferred range being from 1O0C to 150C and isolating the Form III from the reaction mixture.
Any suitable alcohol may be used a solvent, but it is preferred to use ethanol.
The crystalline minocycline bases in Forms I, Il and III obtained by the processes described above have a high purity with all the impurities controlled, especially 4-epi minocycline, which is typically below 1. 2% w/w (ie by weight of the base).
In another aspect, therefore, the invention provides crystalline minocycline base substantially free of 4-epi minocycline. By substantially free, we mean that no more than about 1. 2% impurity by weight of the polymorph (w/w) is present. Preferably the impurity level is less than 1. 2% w/w.
In a further aspect, therefore, the invention provides crystalline minocycline base comprising less than 1.2% w/w (by weight of the base) of 4-epi minocycline. Another aspect of the invention provides processes for preparing amorphous minocycline base on an industrial scale, wherein the minocycline base is obtained in high purity, especially maintaining low levels of the content of 4-epi-minocycline.
In one aspect, there is provided a process for preparing amorphous minocycline base, which process comprises spray drying a solution or suspension of minocycline, in an organic solvent, preferably chosen from methyl tert-butyl ether, dichloromethane or isopropyl acetate
A preferred process for preparing amorphous minocycline base comprises:
1) dissolving minocycline base in one or more organic solvents to form a solution or a suspension
2) spray drying the solution or suspension obtained in step 1 )
3) optionally drying the amorphous minocycline base so obtained , if necessary under vacuum, at a temperature of from 250C to 450C, preferably from 350C to 45 0C.
Any suitable solvent may be used, and preferred solvents include methyl tert-butyl ether, dichloromethane or isopropyl acetate.
Any suitable technique for the spray drying may be used. For example, conventional spray drying techniques (as will be clear to those skilled in the art) may be employed.
EXAMPLES
The following examples are provided to illustrate the present invention and do not in any way limit its scope.
EXAMPLE 1 : Preparation of Form I of crystalline minocycline base Amorphous minocycline base (0.5g) is suspended in methyl tert-butyl ether (4ml) and the resulting heterogeneous mixture stirred for about 2 hours at a temperature between O0C and 3O0C, preferably between 1O0C and 150C.
The product is filtered, washed with methyl tert-butyl ether (1 ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
Yield: 0.38g
The XRPD pattern and infrared are presented in Fig 1 and Fig .2. 4-epi minocycline: 0.06% in area (HPLC)
Melting point: 1130C
EXAMPLE 2: Preparation of Form I of crystalline minocycline base
Amorphous minocycline base (0.5g) is dissolved in methyl tert-butyl ether (6ml) and the resulting solution stirred at a temperature between O0C and 3O0C, preferably between 1O0C and 150C.
After about 5 minutes Form I of crystalline minocycline base precipitates from the solution.
The resulting suspension is filtered, washed with methyl tert-butyl ether (1 ml) and dried under vacuum at about 45°C-50°C to yield Form I of crystalline minocycline base.
Yield: 0.45g.
Melting point: 1130C
EXAMPLE 3: Preparation of Form Il of crystalline minocycline base Amorphous minocycline base (2Og) is suspended in ethyl acetate (160ml) and the resulting heterogeneous mixture stirred for about 3 hours at a temperature between O0C and 3O0C, preferably between 1O0C and 150C.
The product is filtered, washed with ethyl acetate (10ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
Yield: 17. 4g
HPLC purity: 99.5% in area 4-epi minocycline: 0.11% in area.
Melting point: 1870C
The XRPD pattern and infrared are presented in Fig.3 and Fig.4.
EXAMPLE 4: Preparation of Form Il of crystalline minocycline base
Amorphous minocycline base (5 g) is dissolved in ethyl acetate (40ml) and the resulting solution stirred for about 3 hours at a temperature between O0C and 3O0C, preferably between 1O0C and 150C whereupon Form Il of crystalline minocycline base precipitated.
The product is filtered, washed with ethyl acetate (5ml) and dried under vacuum at about 45°C-50°C to yield Form Il of crystalline minocycline base.
Yield: 3.2g
Melting point: 1870C.
EXAMPLE 5: Preparation of Form III of minocycline base
Amorphous minocycline base (0.5g) is suspended in ethyl alcohol (2.5ml) and the resulting heterogeneous mixture stirred for at least 10 hours at a temperature between O0C and 3O0C preferably between 1O0C and 150C. The product is filtered, washed with ethyl alcohol (0.5ml) and dried under vacuum at about 45°C-50°C to yield Form III of crystalline minocycline base.
Yield: 0.44g The XRPD pattern and infrared are presented in Fig.5 and Fig.6. 4-epi minocycline: 0.12% in area (HPLC) Melting point: 193°.
EXAMPLE 6: Preparation of amorphous minocycline base
A solution of minocycline base in dichloromethane, isopropyl acetate or methyl tert- butyl ether was isolated by spray drying in conventional spray drying equipment using an inlet temperature between 450C and 1050C, and an outlet temperature between 3O0C and 750C.
The isolated product can be used directly to obtain any of the Forms of crystalline minocycline base or can be subjected to a post drying step under vacuum at about 450C to yield pure amorphous minocycline base.
Yield: 24.5 g
HPLC purity: 98.6% in area
The XRPD pattern and infra red are presented in Fig 7 and Fig 8.

Claims

1. Minocycline base characterized by being crystalline.
2. Crystalline minocycline base, Form I, characterised by an X-ray diffraction pattern having peaks at 5.2, 7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8, 19.3, 19.5, 20.7, 21.3, 21.8, 22.3, 23.1 , 24.0, 25.3, 25.7 and 26.5 ± 0.2° 2Θ, as given in Fig.1.
3. Crystalline minocycline base, Form I, according to claim 2 further characterized by an infrared spectrum having peaks at 1646,1602, 1581 , 1470, 1397, 1364, 1286,
1218, 1182, 1134, 1072, 1061 , 1023, 1001 , 969, 950, 874, 850, 716, 636, 620 and 545 ± 4 cm"1 as given in Fig. 2.
4. A process for preparing crystalline minocycline base, Form I, which process comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallization from the mixture.
5. A process according to claim 4, wherein the organic solvent is methyl tert-butyl ether.
6. Crystalline minocycline base, Form II, characterised by an X-ray diffraction pattern having peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1, 17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1 , 27.5, 28.0 and 29.1 ± 0.2° 2Θ, as given in Fig.3.
7. Crystalline minocycline base, Form II, according to claim 6 further characterised by an infrared spectrum having peaks at 1644, 1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287, 1251 , 1217, 1186, 1 166, 1136, 1061 , 999, 970, 874, 716, 621 and 585 ± 4 cm"1, as given in Fig. 4.
8. A process for preparing crystalline minocycline, base Form II, which process comprises dissolving and/ or suspending amorphous minocycline base in an organic solvent chosen from esters followed by crystallization from the mixture.
9. A process according to claim 8, wherein the organic solvent is ethyl acetate.
10. Crystalline minocycline base, Form III, characterised by an X-ray diffraction 5 pattern having peaks at 6.5, 10.0, 13.2, 15.1 , 16.5, 17.9, 19.6, 20.2, 21.1 , 22.3, 23.7,
24.8, 26.4, 28.1 and 30.5 ± 0.2° 2Θ, as given in Fig. 5.
11. Crystalline minocycline base, Form III, according to claim 10 further characterised by an infrared spectrum having peaks at 1647, 1605, 1581 , 1470, 1399,
10 1307, 1286, 1251 , 1216, 1195, 1179, 1136, 1094, 1058, 1024, 1000, 973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515, 496 and 413 ± 4 crrϊ1, as given in Fig. 6.
12. A process for preparing crystalline minocycline base, Form III, which process comprises dissolving and/ or suspending amorphous minocycline base in an organic
15 solvent chosen from alcohols followed by crystallization from the mixture.
13. A process according to claim 12, wherein the organic solvent is ethanol.
14. A process for preparing amorphous minocycline base, which process comprises 20 spray drying a solution of minocycline in an organic solvent.
15. A process according to claim 14, wherein the solvent is methyl tert-butyl ether, dichloromethane or isopropyl acetate.
25 16. A process according to any one of claims 4-5, 8-9 or 12-13, wherein the content of 4-epi minocycline is below 1 .2% w/w.
17. Crystalline minocycline base substantially free of 4-epi minocycline.
30 18. Crystalline minocycline base according to claim 16 comprising less than 1.2% w/w of 4-epi minocycline.
PCT/GB2008/000625 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation WO2008102161A2 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
RU2009135403/04A RU2485095C2 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and methods for production thereof
CA2722496A CA2722496C (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
ES08709507.1T ES2610434T3 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and preparation procedures
NZ579626A NZ579626A (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
BRPI0807319-8A BRPI0807319B1 (en) 2007-02-23 2008-02-22 CRYSTALLINE MINOCYCLINE BASE FORM 1, PROCESS TO PREPARE CRYSTALLINE MINOCYCLINE BASE FORM I, CRYSTALLINE MINOCYCLINE BASE FORM II, PROCESS TO PREPARE CRYSTALLINE MINOCYCLINE BASE FORM II, CRYSTALLINE MINOCYCLINE BASE FORM III AND PROCESS TO PREPARE CRYSTALLINE MINOCYCLINE BASE FORM III
EP08709507.1A EP2125705B1 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
AU2008217619A AU2008217619B2 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
CN2008800059328A CN101679218B (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
BR122021000846-9A BR122021000846B1 (en) 2007-02-23 2008-02-22 PROCESS FOR PREPARING AMORPHIC MINOCYCLINE BASE
DK08709507.1T DK2125705T3 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for their preparation
MX2009008980A MX2009008980A (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation.
US12/528,209 US8258327B2 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
JP2009550320A JP2010519247A (en) 2007-02-23 2008-02-22 Crystalline minocycline base and method for producing the same
IL200544A IL200544A0 (en) 2007-02-23 2009-08-23 Crystalline minocycline base and processes for its preparation
NO20092960A NO20092960L (en) 2007-02-23 2009-09-04 Crystalline minocycline base and processes for its preparation
US13/599,116 US9416097B2 (en) 2007-02-23 2012-08-30 Crystalline minocycline base and processes for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT103661A PT103661B (en) 2007-02-23 2007-02-23 MINOCYCINE PREPARATION PROCESS CRYSTALLINE
PT103661 2007-02-23

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US12/528,209 A-371-Of-International US8258327B2 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation
US13/599,116 Division US9416097B2 (en) 2007-02-23 2012-08-30 Crystalline minocycline base and processes for its preparation

Publications (3)

Publication Number Publication Date
WO2008102161A2 true WO2008102161A2 (en) 2008-08-28
WO2008102161A9 WO2008102161A9 (en) 2008-11-13
WO2008102161A3 WO2008102161A3 (en) 2009-01-08

Family

ID=39432804

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/000625 WO2008102161A2 (en) 2007-02-23 2008-02-22 Crystalline minocycline base and processes for its preparation

Country Status (20)

Country Link
US (2) US8258327B2 (en)
EP (1) EP2125705B1 (en)
JP (4) JP2010519247A (en)
KR (1) KR101391132B1 (en)
CN (1) CN101679218B (en)
AU (1) AU2008217619B2 (en)
BR (2) BRPI0807319B1 (en)
CA (2) CA2722496C (en)
DK (1) DK2125705T3 (en)
ES (1) ES2610434T3 (en)
HU (1) HUE033030T2 (en)
IL (1) IL200544A0 (en)
MX (2) MX2009008980A (en)
NO (1) NO20092960L (en)
NZ (1) NZ579626A (en)
PL (1) PL2125705T3 (en)
PT (1) PT103661B (en)
RU (2) RU2577331C2 (en)
WO (1) WO2008102161A2 (en)
ZA (1) ZA200906517B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010084325A3 (en) * 2009-01-23 2010-09-23 Hovione Inter Ltd Process for isolating tigecycline
WO2010149980A2 (en) 2009-06-26 2010-12-29 Hovione Inter Limited Topical formulation containing a tetracycline and a method of treating skin infections using the same
US8258327B2 (en) 2007-02-23 2012-09-04 Hovlone Inter Limited Crystalline minocycline base and processes for its preparation
US8268804B2 (en) 2005-06-24 2012-09-18 Medicis Pharmaceutical Corporation Minocycline oral dosage forms for the treatment of acne
WO2013095169A1 (en) 2011-12-19 2013-06-27 Instituto Superior Técnico Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide
US8722650B1 (en) 2005-06-24 2014-05-13 Medicis Pharmaceutical Corporation Extended-release minocycline dosage forms
US9192615B2 (en) 2008-08-06 2015-11-24 Medicis Pharmaceutical Corporation Method for the treatment of acne and certain dosage forms thereof
WO2016128760A1 (en) 2015-02-13 2016-08-18 Hovione Scientia Limited New polymorphic forms of minocycline base and processes for their preparation
US9561241B1 (en) 2011-06-28 2017-02-07 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for minocycline
WO2017097891A1 (en) * 2015-12-10 2017-06-15 Sandoz Ag Crystalline eravacycline

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL152486A0 (en) 2002-10-25 2003-05-29 Meir Eini Alcohol-free cosmetic and pharmaceutical foam carrier
US10117812B2 (en) 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US9265725B2 (en) 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
US7700076B2 (en) 2002-10-25 2010-04-20 Foamix, Ltd. Penetrating pharmaceutical foam
US7704518B2 (en) 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US20080138296A1 (en) 2002-10-25 2008-06-12 Foamix Ltd. Foam prepared from nanoemulsions and uses
KR101108439B1 (en) 2002-10-25 2012-01-31 포믹스 리미티드 Cosmetic and pharmaceutical foam
US20080260655A1 (en) 2006-11-14 2008-10-23 Dov Tamarkin Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses
US8636982B2 (en) 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
WO2009069006A2 (en) 2007-11-30 2009-06-04 Foamix Ltd. Foam containing benzoyl peroxide
WO2009072007A2 (en) 2007-12-07 2009-06-11 Foamix Ltd. Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof
CA2760186C (en) 2009-04-28 2019-10-29 Foamix Ltd. Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof
WO2011013009A2 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses
CA2769677A1 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses
US9849142B2 (en) 2009-10-02 2017-12-26 Foamix Pharmaceuticals Ltd. Methods for accelerated return of skin integrity and for the treatment of impetigo
EP2482788B1 (en) 2009-10-02 2022-12-14 Journey Medical Corporation Topical tetracycline compositions
CN104151186B (en) * 2014-08-11 2016-06-15 重庆福安药业(集团)股份有限公司 The stereoselectivity preparation method of Tigecycline impurity
CN107708665B (en) 2015-03-23 2022-07-22 贝尔生物制药有限公司 Pharmaceutical tetracycline compositions for dermatological use
US10398641B2 (en) 2016-09-08 2019-09-03 Foamix Pharmaceuticals Ltd. Compositions and methods for treating rosacea and acne
WO2021191273A1 (en) 2020-03-24 2021-09-30 Hovione Scientia Limited Compositions for use in treating meibomian gland dysfunction
WO2022043457A1 (en) 2020-08-27 2022-03-03 Hovione Scientia Limited Methods and compositions for treating rosacea

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014154A2 (en) * 2005-07-21 2007-02-01 Paratek Pharmaceuticals, Inc. 10-substituted tetracyclines and methods of use thereof

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US299111A (en) * 1884-05-27 Process of and apparatus
US3148212A (en) * 1961-12-22 1964-09-08 American Cyanamid Co Reductive alkylation process
USRE26253E (en) * 1963-05-17 1967-08-15 And z-alkylamino-g-deoxytetracycline
US3526629A (en) * 1968-04-02 1970-09-01 American Cyanamid Co Beta-hydroxyethylpiperazinocarboxymethyl - 7 - dimethylamino - 6 - deoxy-6-demethyltetracycline
JPS5245716B1 (en) * 1970-07-10 1977-11-17
CA999855A (en) * 1972-09-18 1976-11-16 Societa' Farmaceutici Italia S.P.A. Process for the preparation of tetracyclines derivatives in the 7 position
CN85101404A (en) * 1985-05-16 1987-01-17 帝人株式会社 The production process of cephalosporins derivatives
JPH0737433B2 (en) * 1987-06-11 1995-04-26 協和醗酵工業株式会社 Method for producing 7-amino-6-demethyl-6-deoxytetracycline
US5202449A (en) * 1987-07-28 1993-04-13 Nippon Kayaku Kabushiki Kaisha Process for purifying 7-dimethylamino-6-demethyl-6-deoxytetracycline
US4918208A (en) * 1987-07-28 1990-04-17 Nippon Kayaku Kabushiki Kaisha Process for producing 7-dimethylamino-6-demethyl-6-deoxytetracycline
JPH04235188A (en) * 1990-06-19 1992-08-24 Takeda Chem Ind Ltd Crystal of penem compound, production thereof and antimicrobial agent
US5262173A (en) * 1992-03-02 1993-11-16 American Cyanamid Company Pulsatile once-a-day delivery systems for minocycline
DE4235133A1 (en) * 1992-10-19 1994-04-21 Bayer Ag Crystalline (R) - (-) - 2-cycloheptyl-N-methylsulfonyl- [4- (2-quinolinyl-methoxy) phenyl] acetamide
JP3623531B2 (en) * 1993-06-07 2005-02-23 ビーエーエスエフ アクチェンゲゼルシャフト Process for producing crystalline L-ascorbic acid-2-phosphate magnesium salt
DE69616808T2 (en) * 1995-07-17 2002-05-29 Warner Lambert Co CRYSTALLINES (R- (R *, R *)) - 2- (4-FLUORPHENYL) BETA, DELTA-DIHYDROXY-5- (1-METHYLETHYL) -3-PHENYL-4 - ((PHENYLAMINO) CARBONYL) -1H- PYRROL-1-HEPTANIC CARBONIC ACID HEMI CALCIUM SALT (ATORVASTATIN)
PE20000012A1 (en) 1997-12-22 2000-01-18 Schering Corp COMPOSITION FOR MOLECULAR DISPERSION WITH INCREASED BIODAVAILABILITY
IE991011A1 (en) * 1998-12-01 2000-07-12 Atropos Ltd A Device
CL2004001884A1 (en) * 2003-08-04 2005-06-03 Pfizer Prod Inc DRYING PROCEDURE FOR SPRAYING FOR THE FORMATION OF SOLID DISPERSIONS AMORPHES OF A PHARMACO AND POLYMERS.
AR057649A1 (en) * 2005-05-27 2007-12-12 Wyeth Corp SOLID CRYSTALINE TIGECICLINE FORMS AND METHODS TO PREPARE THE SAME
PT103661B (en) 2007-02-23 2010-09-07 Hovione Farmaciencia S A MINOCYCINE PREPARATION PROCESS CRYSTALLINE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014154A2 (en) * 2005-07-21 2007-02-01 Paratek Pharmaceuticals, Inc. 10-substituted tetracyclines and methods of use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BERNARDI L ET AL: "Tetracycline derivatives" FARMACO, EDIZIONE SCIENTIFICA, SOCIETA CHIMICA ITALIANA, PAVIA, vol. 30, no. 9, 1 January 1975 (1975-01-01), pages 736-741, XP009101407 ISSN: 0430-0920 *
CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS" TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163-208, XP001156954 ISSN: 0340-1022 *
CHURCH ET AL.: "Synthesis of 7-Dimethylamino-6-demethyl-6-deoxytetracyc line (Minocycline) via 9-nitro-6-demethyl-6-deoxytetracycline." J. ORG. CHEM., vol. 36, no. 5, 1971, pages 723-725, XP002485261 *
YU L: "AMORPHOUS PHARMACEUTICAL SOLIDS: PREPARATION, CHARACTERIZATION AND STABILIZATION" ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER BV, AMSTERDAM, NL, vol. 48, no. 1, 16 May 2001 (2001-05-16), pages 27-42, XP009065056 ISSN: 0169-409X *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8268804B2 (en) 2005-06-24 2012-09-18 Medicis Pharmaceutical Corporation Minocycline oral dosage forms for the treatment of acne
US8722650B1 (en) 2005-06-24 2014-05-13 Medicis Pharmaceutical Corporation Extended-release minocycline dosage forms
US9416097B2 (en) 2007-02-23 2016-08-16 Hovione Scientia Limited Crystalline minocycline base and processes for its preparation
US8258327B2 (en) 2007-02-23 2012-09-04 Hovlone Inter Limited Crystalline minocycline base and processes for its preparation
US9192615B2 (en) 2008-08-06 2015-11-24 Medicis Pharmaceutical Corporation Method for the treatment of acne and certain dosage forms thereof
JP2015166347A (en) * 2009-01-23 2015-09-24 ホビオネ インテル リミテッド Process for isolating tigecycline
JP2012515753A (en) * 2009-01-23 2012-07-12 ホビオネ インテル リミテッド Method for isolating tigecycline
WO2010084325A3 (en) * 2009-01-23 2010-09-23 Hovione Inter Ltd Process for isolating tigecycline
US9187410B2 (en) 2009-01-23 2015-11-17 Hovione Inter Limited Process for isolating tigecycline and tigecycline made therefrom
WO2010149980A3 (en) * 2009-06-26 2011-03-24 Hovione Inter Limited Topical formulation containing a tetracycline and a method of treating skin infections using the same
WO2010149980A2 (en) 2009-06-26 2010-12-29 Hovione Inter Limited Topical formulation containing a tetracycline and a method of treating skin infections using the same
US9561241B1 (en) 2011-06-28 2017-02-07 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for minocycline
WO2013095169A1 (en) 2011-12-19 2013-06-27 Instituto Superior Técnico Crystalline minocycline thermo-resistant obtained by recrystallization with carbon dioxide
WO2016128760A1 (en) 2015-02-13 2016-08-18 Hovione Scientia Limited New polymorphic forms of minocycline base and processes for their preparation
EP3354637A1 (en) * 2015-02-13 2018-08-01 Hovione Scientia Limited New polymorphic forms of minocycline base and processes for their preparation
US10351516B2 (en) 2015-02-13 2019-07-16 Hovione Scientia Limited Polymorphic forms of minocycline base and processes for their preparation
US10351515B2 (en) 2015-02-13 2019-07-16 Hovione Scientia Limited Polymorphic forms of minocycline base and processes for their preparation
AU2016217617B2 (en) * 2015-02-13 2019-10-03 Hovione Scientia Limited New polymorphic forms of minocycline base and processes for their preparation
WO2017097891A1 (en) * 2015-12-10 2017-06-15 Sandoz Ag Crystalline eravacycline

Also Published As

Publication number Publication date
MX340539B (en) 2016-07-13
PT103661A (en) 2008-08-25
US20100286417A1 (en) 2010-11-11
RU2009135403A (en) 2011-03-27
JP2014169319A (en) 2014-09-18
US8258327B2 (en) 2012-09-04
CA2722496A1 (en) 2008-08-28
IL200544A0 (en) 2010-05-17
HUE033030T2 (en) 2017-11-28
CN101679218A (en) 2010-03-24
JP2010519247A (en) 2010-06-03
KR20100014520A (en) 2010-02-10
KR101391132B1 (en) 2014-05-02
RU2013112021A (en) 2014-09-27
CN101679218B (en) 2013-10-30
RU2485095C2 (en) 2013-06-20
US20130030195A1 (en) 2013-01-31
PL2125705T3 (en) 2017-02-28
WO2008102161A9 (en) 2008-11-13
RU2577331C2 (en) 2016-03-20
DK2125705T3 (en) 2017-01-16
CA2722496C (en) 2014-06-10
EP2125705A2 (en) 2009-12-02
NO20092960L (en) 2009-11-20
BR122021000846B1 (en) 2021-08-10
CA2835788C (en) 2018-03-27
MX2009008980A (en) 2009-11-11
BRPI0807319A2 (en) 2017-05-02
AU2008217619A1 (en) 2008-08-28
JP2019142882A (en) 2019-08-29
PT103661B (en) 2010-09-07
EP2125705B1 (en) 2016-10-12
AU2008217619B2 (en) 2013-01-10
WO2008102161A3 (en) 2009-01-08
NZ579626A (en) 2011-12-22
JP2017039742A (en) 2017-02-23
CA2835788A1 (en) 2008-08-28
ZA200906517B (en) 2010-09-29
US9416097B2 (en) 2016-08-16
ES2610434T3 (en) 2017-04-27
BRPI0807319B1 (en) 2021-08-10

Similar Documents

Publication Publication Date Title
CA2722496C (en) Crystalline minocycline base and processes for its preparation
JP6594917B2 (en) Optimal synthesis of pure nonpolymorphic crystalline bile acids with a given particle size
CA2890961A1 (en) Novel polymorphs of azilsartan medoxomil
TWI740922B (en) A new crystalline form of obeticholic acid and preparation method thereof
WO2005123721A2 (en) Amorphous and polymorphic forms of candesartan cilexetil
US7745429B2 (en) Crystal forms of olanzapine and processes for their preparation
WO2014195977A2 (en) Novel polymorphs of vismodegib
US20160222053A1 (en) Polymorphic form of sodium hyodeoxycholate (nahdc) and its preparation process
WO2009156279A2 (en) Process for the preparation of clopidogrel hydrogen sulfate crystalline form i
CN109790172B (en) Process for the isolation and purification of naltrexone
CN117700354A (en) Crystal form of raffinancin and preparation method thereof
EP1785411A1 (en) Protriptyline hydrochloride crystalline form
TW201323407A (en) Process for the preparation of 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and intermediates thereof
WO2005100302A1 (en) Solid state forms of (-)-(1r,2s)-2-amino-4-methylene-cyclopentanecarboxylic acid

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880005932.8

Country of ref document: CN

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

Ref document number: 08709507

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2009550320

Country of ref document: JP

Ref document number: MX/A/2009/008980

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 200544

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008217619

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 3199/KOLNP/2009

Country of ref document: IN

REEP Request for entry into the european phase

Ref document number: 2008709507

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 579626

Country of ref document: NZ

Ref document number: 2008709507

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1020097019750

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2009135403

Country of ref document: RU

ENP Entry into the national phase

Ref document number: 2008217619

Country of ref document: AU

Date of ref document: 20080222

Kind code of ref document: A

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 12528209

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2722496

Country of ref document: CA

ENP Entry into the national phase

Ref document number: PI0807319

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090824