EP0000276B1 - Forme cristalline nouvelle du benoxaprofen, procédés pour sa préparation et compositions pharmaceutiques la contenant - Google Patents

Forme cristalline nouvelle du benoxaprofen, procédés pour sa préparation et compositions pharmaceutiques la contenant Download PDF

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Publication number
EP0000276B1
EP0000276B1 EP78300082A EP78300082A EP0000276B1 EP 0000276 B1 EP0000276 B1 EP 0000276B1 EP 78300082 A EP78300082 A EP 78300082A EP 78300082 A EP78300082 A EP 78300082A EP 0000276 B1 EP0000276 B1 EP 0000276B1
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EP
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Prior art keywords
benoxaprofen
bands
novel
preparing
pharmaceutical
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Expired
Application number
EP78300082A
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German (de)
English (en)
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EP0000276A1 (fr
Inventor
Roy Sherlock
Terence Alan Hicks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lilly Industries Ltd
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Lilly Industries Ltd
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • 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]

Definitions

  • This invention relates to a novel polymorphic form of a pharmacologically active substance and to pharmaceutical formulations containing the novel polymorph.
  • An object of the present invention is to provide a polymorphic form of benoxaprofen which has sufficient stability to be useful in the production of pharmaceutical formulations having a satisfactory shelf life.
  • Form II characterised as above, can also be distinguished from Form I by its infra red spectrum.
  • a Perkin Elmer 297 spectrophotometer with benoxaprofen homogeneously dispersed in a potassium bromide disc, the following differences can be observed:
  • Infra red analysis which will be the usual method of assay of commercial material, is sensitive enough to detect as little as 10% by weight of Form I in batches of Form II material. Batches of Form II assayed by this spectral mode of analysis have proved to be quite satisfactory in pharmaceutical formulations such as tablets, capsules or suspensions, such formulations not deteriorating on storage.
  • Form II contaminated with less than 10% by weight of Form I.
  • a pharmaceutical formulation comprising as an active material Form II associated with a pharmaceutically-acceptable carrier therefor.
  • the Form II polymorph in the above formulation should be pure as determined by the infra red assay technique described previously, i.e. it should contain less than 10% by weight of Form I.
  • Form I can be converted to Form II by heating in a fluid bed dryer at a temperature of approximately 115°C for upwards of 3 hours.
  • Form II may be prepared by slow and controlled crystallisation from solutions of benoxaprofen in n-butyl acetate.
  • Form II crystals of benoxaprofen can also be obtained by thermal decomposition at temperatures in the range 90-160°C of the ammonium salt of benoxaprofen.
  • benoxaprofen ammonium salt is isolated directly from the hydrolysis of 2-(4-chlorophenyl)-a-methyl-5-benzoxazolylacetonitrile as an insoluble precipitate.
  • the precipitate is collected and dried at a temperature in the above range, during which drying period the ammonium salt decomposes to yield dry benoxaprofen Form II crystals. Drying is continued until the decomposition of the ammonium salt is substantially complete.
  • the yield of Form II material is usually in the range 95-98 percent.
  • the ammonium salt can be suspended in a solvent boiling in the range 90-160°C and the resulting suspension or slurry heated, preferably by reflux; i.e. at the boiling point of the solvent, until the ammonium salt is substantially completely decomposed to ammonia and the free purified alkanoic acid.
  • the purified acid thus produced is substantially insoluble in the solvent used to slurry the ammonium salt (n-octane for example)
  • benoxaprofen Form II will be obtained as from heating the salt in the absence of a solvent.
  • benoxaprofen is soluble in the solvent used to slurry the ammonium salt, (n-butyl acetate for example), a recrystallized product will be obtained.
  • benoxaprofen can be separated from the solvent by decantation or filtration. If benoxaprofen is soluble in the solvent employed, the solution is ordinarily concentrated and/or chilled to increase crystallisation and further crystals are obtained from the mother liquor.
  • the filter cake was then dissolved in 48.3 litres of dimethylformamide at 55°C and the resulting solution diluted with about 180 litres of acetone.
  • the resulting solution was filtered, the filtrate collected and about 11 litres of 28 percent aqueous ammonium hydroxide added very slowly to the filtrate maintained at about 35°C over a period of about t hour.
  • the ammonium salt of 2-(4-chlorophenyl)-a-methyl-5-benz- oxazolylacetic acid slowly precipitated yielding a slurry.
  • the pH of the slurry was checked and found to be about 9.
  • the slurry was next chilled in an ice-water mixture to about 0°C and the precipitated ammonium salt separated by filtration.
  • the filter cake was washed with cold acetone (0°C) and the washed filter cake dried at 125°C for 3 hours in a tray dryer. During this heating and drying period, the ammonium salt decomposed yielding 2-(4-chlorophenyl)-a-methyl-5-benz- oxazolylacetic acid as Form II. 29.65 kg of purified free acid were obtained assaying at about 95 percent purity. The presence of Form II was demonstrated using X-ray powder diffraction and infra red analysis.
  • Form II (97% or higher purity) 6 hours at 95°C, 2.5 hours at 125°C, 1.5 hours at 140°C, 0.5 hours at 155°C, i.e. the higher the temperature used the faster will be the polymorphic transformation from Form I to Form II.
  • the Form II and the starch were admixed and granulated with the polyvinylpyrrolidone as a 20% solution In water. Additional water was then added to form a suitable granulation which was passed through a stainless steel mesh screen with 1 mm apertures. The resultant granules were dried on a tray in a steam oven at 50 to 60°C. The dried granules were then passed through a screen (0.5 mm apertures) mixed with the magnesium stearate and compressed into tablets.
  • Tablets thus prepared were stored at 4, 25 and 40°C for two years. No deterioration in the physical characteristics of the tablets or in their appearance was noted over this period of time.
  • Benoxaprofen Form I was packed into glass ampoules (5 ml) and then subjected to cyclic temperature changes over two years.
  • the weekly cycling programme adopted was that specified below:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (8)

1. Forme Il de bénoxaprofen, le bénoxaprofen étant l'acide 2-(4-chlorophényl)-a-méthyl-5-benzoxazolylacétique, tandis que les cristaux de la forme II présentent le diagramme de diffraction de poudre ci-après en utilisant des radiations de cuivre-nickel filtrées à λ=1,5405 A.
Figure imgb0006
2. Forme Il de bénoxaprofen contaminée avec moins de 10% en poids de la forme I; la forme II pouvant être distinguée de la forme I par son spectre d'absorption des rayons infrarouges lorsqu'elle est dispersée de manière homogène dans un disque de bromure de potassium et en employant un spectrophotomètre "Perkin Elmer 297", les différences observées étant les suivantes:
(a) la forme I présente une nette bande d'intensité moyenne à 880 cm-1, tandis que la forme Il présente une bande semblable à 885 cm-1;
(b) dans la zone de 1.200-1.330 cm-1, les deux formes présentent une localisation analogue de bandes, cependant que les intensités diffèrent, les bandes de la forme I à 1.220 et 1.250 cm-1 étant beaucoup plus intenses que les autres tandis que, dans la forme II, toutes les bandes ont une intensité semblable; et
(c) une forte bande proche de 1.700 cm-1 étant beaucoup plus nette pour la forme I que pour la forme Il.
3. Formulation pharmaceutique de bénoxaprofen en association avec un support pharma- ceutiquement acceptable pour ce dernier, caractérisée en ce que le bénoxaprofen est la forme Il de bénoxaprofen selon les définitions données dans la revendication 1 ou 2.
4. Formulation pharmaceutique suivant la revendication 3, sous forme d'un comprimé.
5. Forme Il de bénoxaprofen selon les définitions données dans la revendication 1 ou 2, utilisée comme produit pharmaceutique.
6. Procédé de préparation d'une formulation pharmaceutique de bénoxaprofen, caractérisé en ce qu'on mélange la forme Il de bénoxaprofen selon les définitions données dans la revendication 1 ou 2, avec un support pharmaceutique pour cette dernière.
7. Procédé de préparation de la forme Il de bénoxaprofen, caractérisé en ce qu'il consiste à effectuer la cristallisation lente et contrôlée du bénoxaprofen hors d'une solution dans de l'acétate de n-butyle.
8. Procédé de préparation de la forme Il de bénoxaprofen, caractérisé en ce qu'il consiste à décomposer thermiquement le sel d'ammonium de bénoxaprofen à une température se situant dans l'intervalle de 90-160°C.
EP78300082A 1977-06-28 1978-06-27 Forme cristalline nouvelle du benoxaprofen, procédés pour sa préparation et compositions pharmaceutiques la contenant Expired EP0000276B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2690777 1977-06-28
GB26907/77A GB1590587A (en) 1977-06-28 1977-06-28 Benoxaprofen

Publications (2)

Publication Number Publication Date
EP0000276A1 EP0000276A1 (fr) 1979-01-10
EP0000276B1 true EP0000276B1 (fr) 1982-09-01

Family

ID=10251100

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78300082A Expired EP0000276B1 (fr) 1977-06-28 1978-06-27 Forme cristalline nouvelle du benoxaprofen, procédés pour sa préparation et compositions pharmaceutiques la contenant

Country Status (17)

Country Link
EP (1) EP0000276B1 (fr)
JP (1) JPS5411224A (fr)
AT (1) AT360008B (fr)
AU (1) AU518403B2 (fr)
BE (1) BE868522A (fr)
CH (1) CH631449A5 (fr)
DE (2) DE2862013D1 (fr)
DK (1) DK145419C (fr)
FI (1) FI69453C (fr)
FR (1) FR2396004A1 (fr)
GB (1) GB1590587A (fr)
IE (1) IE47009B1 (fr)
IL (1) IL55015A (fr)
IT (1) IT1105065B (fr)
LU (1) LU79879A1 (fr)
NZ (1) NZ187674A (fr)
ZA (1) ZA783660B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021116820A1 (fr) * 2019-12-10 2021-06-17 Aurobindo Pharma Limited Procédé amélioré pour la préparation de benoxaprofène

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1435721A (en) * 1972-05-18 1976-05-12 Lilly Industries Ltd Benzoxazole derivatives
US3888864A (en) 1973-06-29 1975-06-10 Hoffmann La Roche Amino lower alkyl ether derivatives of opium alkaloids
GB1495488A (en) * 1976-06-23 1977-12-21 Ippco Int Pharma Patents Co Es Optically active 2-(2-phenyl-5-benzoxazolyl)propionic acids
IT1099589B (it) * 1978-08-04 1985-09-18 Ravizza Spa Processo per la preparazione di derivati dell'acido benzoxazolil propionico
IT1157295B (it) * 1982-07-19 1987-02-11 Ravizza Spa Processo perfezionato per la preparazione di derivati dell'acido benzoxazolil propionico
UA83620C2 (ru) 2001-12-05 2008-08-11 Уайт Замещенные бензоксазолы и их аналоги как эстрогенные агенты
DE102022117931A1 (de) 2022-07-18 2024-01-18 HUECK System GmbH & Co. KG Profilanordnung mit wärmedämmung
US11981645B1 (en) 2023-10-10 2024-05-14 King Faisal University N′-(2-naphthoyloxy)-2-(benzo[d]oxazol-2-yl)acetimidamide as antimicrobial compound

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1435721A (en) * 1972-05-18 1976-05-12 Lilly Industries Ltd Benzoxazole derivatives
GB1488003A (en) * 1973-10-23 1977-10-05 Lilly Industries Ltd 1,2-benzisoxazole derivatives processes for their preparation and their use as pharmaceuticals
US4087437A (en) * 1976-09-07 1978-05-02 Eli Lilly And Company 2-Phenyl-5-benzoxazolylalkanoic acid purification process

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021116820A1 (fr) * 2019-12-10 2021-06-17 Aurobindo Pharma Limited Procédé amélioré pour la préparation de benoxaprofène

Also Published As

Publication number Publication date
EP0000276A1 (fr) 1979-01-10
CH631449A5 (fr) 1982-08-13
IT7850048A0 (it) 1978-06-27
JPS5411224A (en) 1979-01-27
FI69453C (fi) 1986-02-10
FI782043A (fi) 1978-12-29
ZA783660B (en) 1979-06-27
BE868522A (fr) 1978-12-27
DE2828074A1 (de) 1979-01-11
IE47009B1 (en) 1983-11-30
DE2862013D1 (en) 1982-10-28
JPS6231714B2 (fr) 1987-07-09
FR2396004B1 (fr) 1981-09-18
GB1590587A (en) 1981-06-03
NZ187674A (en) 1980-11-14
DK145419B (da) 1982-11-15
IE781277L (en) 1978-12-28
AT360008B (de) 1980-12-10
ATA466178A (de) 1980-05-15
IL55015A0 (en) 1978-08-31
DK287578A (da) 1978-12-29
LU79879A1 (fr) 1978-12-07
AU518403B2 (en) 1981-10-01
IT1105065B (it) 1985-10-28
IL55015A (en) 1981-11-30
FI69453B (fi) 1985-10-31
AU3750178A (en) 1980-01-03
DK145419C (da) 1983-04-18
FR2396004A1 (fr) 1979-01-26

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