WO2003090730A1 - Nouvelles formes cristallines de celecoxib et d'autres composes - Google Patents

Nouvelles formes cristallines de celecoxib et d'autres composes Download PDF

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Publication number
WO2003090730A1
WO2003090730A1 PCT/GB2002/001902 GB0201902W WO03090730A1 WO 2003090730 A1 WO2003090730 A1 WO 2003090730A1 GB 0201902 W GB0201902 W GB 0201902W WO 03090730 A1 WO03090730 A1 WO 03090730A1
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WO
WIPO (PCT)
Prior art keywords
organic compound
adduct
organic
celecoxib
solvent
Prior art date
Application number
PCT/GB2002/001902
Other languages
English (en)
Inventor
Elias Ndzie
Original Assignee
Generics [Uk] Limited
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 Generics [Uk] Limited filed Critical Generics [Uk] Limited
Priority to AU2002251329A priority Critical patent/AU2002251329A1/en
Priority to PCT/GB2002/001902 priority patent/WO2003090730A1/fr
Publication of WO2003090730A1 publication Critical patent/WO2003090730A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention relates to novel crystalhne forms of organic compounds, particularly those that are pharmaceutically active, processes for preparing such forms, compositions comprising such forms, and uses for such forms and compositions.
  • the manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active drug substance has an irregular crystal ne form.
  • irregularities can cause handling difficulties during the manufacturing process and these can lead to undesirable properties being imparted to the final drug or dosage form.
  • the latter include inconsistent drug substance dissolution rates and the like.
  • an organic compound in a solid crystalline form that affords the compound improved handling properties and/ or improved properties as a pharmaceutical agent.
  • said crystalhne form is particulate and comprises substantially regularly shaped and free flowing crystalhne particles that are preferably more free flowing and regular in shape than previously known forms of the compound.
  • the compound is preferably dry and substantially free of water.
  • the organic compound preferably includes no more than 5, 2, 1, 0.5% water.
  • the organic compound is preferably in the form of an adduct with an organic solvent, preferably a polar organic solvent that is preferably miscible with water.
  • the adduct is preferably a solvate, wherein the solvent is bound into the crystal lattice of the organic compound and cannot be removed by conventional vacuum drying, for example, at a vacuum of down to 50, 40, 35, 30, 25 or 20 mm Hg, preferably 30 mm Hg, at a temperature of up to 20, 25, 35, 40, 45, 50, 55, 60°C, preferably 45 °C.
  • the organic solvent can be dipolar and/or aprotic.
  • the organic compound is preferably soluble in the organic solvent but substantially less soluble or insoluble in water.
  • Organic solvents which form a solvate in accordance with the invention can be identified by routine experimentation.
  • the organic solvent is preferably dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA) or 1- methyl-2-pyrrolidone (NMP).
  • DMSO dimethyl sulfoxide
  • DMA dimethyl acetamide
  • NMP 1- methyl-2-pyrrolidone
  • a plurahty of solvents can be present in the adduct or solvate.
  • the adduct can comprise any ratio between the organic compound and the organic solvent(s), but it is preferably a 1:1 adduct or solvate, in the sense that it includes a 1:1 ratio of molecules of organic compound to solvent molecules in its crystal structure.
  • the adduct or solvate preferably, has a crystal structure that includes a regular array of solvent and organic compound molecules.
  • An example of a drug substance which has an irregular crystalhne structure when prepared by heretofore known techniques, is the selective cyclooxygenase-2 (COX- 2) inhibitor 4-(5-(4-Methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl)benzenesulfonamide which is more commonly known by its generic name Celecoxib.
  • COX-2 selective cyclooxygenase-2
  • the irregular crystalhne shape of Celecoxib prepared by conventional crystallisation techniques can be seen in the scanning electron microscope image represented by Figure 1.
  • the present invention provides a Celecoxib adduct, comprising Celecoxib and an organic solvent, in a sohd crystalhne form.
  • the organic solvent is preferably of the type employed in compounds in accordance with the first aspect of the invention and adducts in accordance with the second aspect of the invention, preferably, have the same properties as those set out above for adducts in accordance with the first aspect of the invention.
  • the organic compound is Celecoxib.
  • organic compounds which may be the subject of the present invention are Rofecoxib, Olanzapine, Zafirlukast, Ondansetron, Clopidogrel, Ticlopidine but the invention can be apphed to any organic compound which has an irregular crystalhne form.
  • the compound can be in the form of a free base or a pharmaceutically acceptable salt or ester, such as a hydrochloride or like acid addition salt.
  • the inventive crystalhne form or adduct is preferably preparable or prepared by a method comprising crystallisation from a solution of the organic compound in the solvent(s), preferably by precipitating said form or adduct from a solution of the organic compound in the organic solvent(s) by the addition of water to the solution.
  • Said method in an embodiment, also comprises the step of drying the precipitate to provide a crystalhne form of the organic compound, or adduct or solvate, in accordance with the invention.
  • the crystalhne form, adduct or solvate can be dried under conventional vacuum drying conditions, for example, under a vacuum of down to 50, 40, 35, 30, 25 or 20 mm Hg, preferably 30 mm Hg, at a temperature of up to 20, 25, 35, 40, 45, 50, 55, 60°C, preferably 45 °C.
  • the crystalhne forms and adducts in accordance with the invention can be used to advantage in the preparation of pharmaceutical dosage or drug forms.
  • the crystalhne forms and adducts in accordance with the invention are free flowing and do not present any of the handhng difficulties associated with irregularly shaped crystals. They, therefore, can be employed in the manufacture of pharmaceuticals that do not suffer from the problems, such as inconsistent drug substance dissolution rates and the hke, that can be manifest in dosage forms manufactured using drug substances that have irregularly shaped crystals.
  • the present invention provides a method of preparing a pharmaceutical dosage form that utilises a crystalhne form or adduct in accordance with the first or second aspect of the invention. It also provides a pharmaceutical dosage form prepared or preparable by such a method.
  • the dosage form is preferably sohd and can comprise a crystalhne form or adduct in accordance with the invention, in addition to one or more conventional pharmaceutically acceptable excipient(s).
  • Preferred dosage forms in accordance with the invention include tablets, capsules and the hke. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry granulation.
  • Capsules are generally formed from a hard gelatine material and can include a conventionally prepared granulate of excipients and a crystalhne form, adduct or solvate in accordance with the invention.
  • the excipients can include lactose, sodium lauryl sulphate, povidoine, croscramellose sodium and magnesium stearate.
  • Crystalhne forms in accordance with the first aspect of the invention can also be used to prepare alternative crystalhne forms of the organic compound in accordance with the first aspect of the invention, which alternative forms are substantially free of bound organic solvent.
  • Crystalhne forms in accordance with the first aspect of the invention that are substantially free of bound organic solvent include less than the amount of solvent which would remain bound within the crystal lattice of the adduct or solvate under conventional vacuumed drying conditions. Typically, this means that the amount of bound organic solvent, on a weight for weight basis, would be less than 2.0%, preferably less than 1.8%, more preferably less than 1.5%, even more preferably less than 1.0%, yet more preferably less than 0.5% and most preferably less than 0.1%.
  • These alternative forms are preferably novel polymorphic forms of the organic compound and they can be prepared by removing the solvent from the adduct, for example, by drying or by the use of a displacing agent, such as water, supercritical carbon dioxide, pyridine or a halogenated solvent.
  • a displacing agent such as water, supercritical carbon dioxide, pyridine or a halogenated solvent.
  • super critical carbon dioxide the flow rate, temperature and pressure of the carbon dioxide should be controlled to give the optimum solvent removal from the organic compound.
  • high pressure carbon dioxide may be used for example at about 2500 psi. Elevated temperatures may also be preferably used such as between 50 to 80°C. More preferably between 55 to 75°C.
  • the absence of organic solvent from these alternative forms can be an advantage in certain circumstances.
  • they can be employed in place of adducts or solvates in accordance with the present invention if the conditions required to formulate a particular dosage form would be potentially detrimental to the stability of such an adduct or solvate.
  • the ability of adducts and solvates in accordance with the invention to facilitate the preparation of solvent free entities in accordance with the first aspect of the invention is a significant advantage.
  • the present invention also provides, in a further aspect, a process for preparing a crystalline organic compound wherein the crystalline form affords the compound improved handhng properties and/or improved properties as a pharmaceutical agent comprising crystalhsing the organic compound or an intermediate to the said organic compound from a first organic solvent.
  • the inventive process may provide a crystalhne organic compound which is an adduct or solvate with a second organic solvent(s).
  • the first and second organic solvent referred to in the above process may be the same solvent.
  • a co-solvent such as water, may be used in the process to facihtate the crystallisation.
  • the inventive process preferably comprises precipitating a crystalhne form, adduct or solvate in accordance with the invention, from a solution of the organic compound in an organic solvent or mixture of solvents by the addition of water to the solution.
  • Said method also comprises the step of drying the precipitate to provide a crystalhne form of the organic compound, adduct or solvate, in accordance with the invention. Drying preferably involves conventional vacuum drying, for example, at a vacuum of down to 50, 40, 35, 30, 25 or 20 mm Hg, preferably 30 mm Hg, at a temperature of up to 20, 25, 35, 40, 45, 50, 55, 60°C, preferably 45 °C.
  • the organic solvent used in processes in accordance with the invention preferably, is a polar organic solvent that is preferably miscible with water.
  • the organic solvent can be dipolar and/or aprotic.
  • the organic compound is preferably soluble in the organic solvent but substantially less soluble or insoluble in water.
  • Organic solvents which form a solvate in accordance with the invention are preferred and can be identified by routine experimentation.
  • the organic solvent is preferably dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA) or 1 -methyl-2-pyrrohdone (NMP).
  • DMSO dimethyl sulfoxide
  • DMA dimethyl acetamide
  • NMP 1 -methyl-2-pyrrohdone
  • Celecoxib is a non-steroidal anti-inflammatory drug used for symptomatic rehef in the treatment of osteoarthritis or rheumatoid arthritis. It is currently available in capsules comprising either 100 mg or 200 mg doses. It is preferred, therefore, that dosages forms in accordance with the present invention, wherein the organic compound is Celecoxib or a Celecoxib solvent adduct or solvate, should include sufficient of the latter to provide a dose of between 50 mg and 300 mg, preferably 100 mg or 200 mg, of the Celecoxib active agent.
  • an organic compound in accordance with the first aspect of the invention wherein said compound is Celecoxib, for the preparation of a medicament for use in treating osteoarthritis or rheumatoid arthritis.
  • Figure 1 A scanning electron microscope image of Celecoxib crystals produced by conventional crystallisation techniques.
  • Figure 2 A scanning electron microscope image of the Celecoxib:DMA adduct prepared in example 1.
  • Figure 3 A scanning electron microscope image of the Celecoxib:DMSO adduct prepared in example 2.
  • Figure 4 A scanning electron microscope image of the Celecoxib:NMP adduct prepared in example 3.
  • FIG. 11 A XRPD diagram of Celecoxib crystals produced by conventional crystallisation techniques.
  • Figure 12 An IR spectrum of Celecoxib crystals produced by conventional crystallisation techniques.
  • the IR spectra were obtained using a Bruker Equinox 55 Attenuated Total Reflectance (ATR).
  • Celecoxib was dissolved into 6mL of DMA under stirring at 45°C (inner temperature) for 5 to 10 minutes. To the clear solution obtained water was added dropwise under stirring. The temperature of the solution rose to
  • the organic solvent forming the adducts in the above examples can be removed by drying or by using a displacing agent to produce further novel crystalhne forms of the organic compound which improve its properties as a pharmaceutical agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé organique sous forme de cristaux solides, cette forme conférant au composé des propriétés de manipulation améliorées et/ou des propriétés améliorées d'agent pharmaceutique. Le composé se présente de préférence sous la forme d'un produit d'addition ou d'un solvate avec un solvant organique.
PCT/GB2002/001902 2002-04-25 2002-04-25 Nouvelles formes cristallines de celecoxib et d'autres composes WO2003090730A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002251329A AU2002251329A1 (en) 2002-04-25 2002-04-25 Novel crystalline forms of celecoxib and other compounds
PCT/GB2002/001902 WO2003090730A1 (fr) 2002-04-25 2002-04-25 Nouvelles formes cristallines de celecoxib et d'autres composes

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PCT/GB2002/001902 WO2003090730A1 (fr) 2002-04-25 2002-04-25 Nouvelles formes cristallines de celecoxib et d'autres composes

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098345B2 (en) 2002-04-29 2006-08-29 TEVA Gyógyszergyár Zárkörüen Müködö Részvénytársaság Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-YL)methyl]-4H-carbazol-4-one

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1287119A (zh) * 2000-09-18 2001-03-14 中国科学院广州化学研究所 赛利可喜的合成方法
WO2001042222A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Formes polymorphes cristallines du celecoxibe
WO2002000627A1 (fr) * 2000-06-26 2002-01-03 Fako Ilaclari A.S. Forme cristalline de celecoxib
WO2002018390A1 (fr) * 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine
WO2002038545A2 (fr) * 2000-10-24 2002-05-16 Finetech Laboratories Ltd. Forme cristalline de solvate d'ethylate de zafirlukast, procede de preparation de cette derniere et compositions pharmaceutiques comprenant cette derniere

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042222A1 (fr) * 1999-12-08 2001-06-14 Pharmacia Corporation Formes polymorphes cristallines du celecoxibe
WO2002000627A1 (fr) * 2000-06-26 2002-01-03 Fako Ilaclari A.S. Forme cristalline de celecoxib
WO2002018390A1 (fr) * 2000-08-31 2002-03-07 Dr. Reddy's Laboratories Ltd. Procede de preparation d'hydrates d'olanzapine et de conversion de ceux-ci en formes cristallines d'olanzapine
CN1287119A (zh) * 2000-09-18 2001-03-14 中国科学院广州化学研究所 赛利可喜的合成方法
WO2002038545A2 (fr) * 2000-10-24 2002-05-16 Finetech Laboratories Ltd. Forme cristalline de solvate d'ethylate de zafirlukast, procede de preparation de cette derniere et compositions pharmaceutiques comprenant cette derniere

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 200143, Derwent World Patents Index; Class B05, AN 2001-398913, XP002224414 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7098345B2 (en) 2002-04-29 2006-08-29 TEVA Gyógyszergyár Zárkörüen Müködö Részvénytársaság Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-YL)methyl]-4H-carbazol-4-one

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