EP0000276A1 - 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 PDFInfo
- Publication number
- EP0000276A1 EP0000276A1 EP78300082A EP78300082A EP0000276A1 EP 0000276 A1 EP0000276 A1 EP 0000276A1 EP 78300082 A EP78300082 A EP 78300082A EP 78300082 A EP78300082 A EP 78300082A EP 0000276 A1 EP0000276 A1 EP 0000276A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- benoxaprofen
- novel
- preparation
- methods
- formulations containing
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 0 C*c(cc1)cc(C2)c1OC2c1ccc(C)cc1 Chemical compound C*c(cc1)cc(C2)c1OC2c1ccc(C)cc1 0.000 description 1
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
- 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 II can be prepared from Form I by heating the latter material at a temperature in the range of. from 90 to 170°C.
- 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. The higher the temperature used the faster will be the polymorphic transformation from Form I to Form II.
- 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, according to the procedure described in United States Patent 4,098,437.
- benoxaprofen ammonium salt is isolated directly from the hydrolysis of 2-p-chlorophenyl)-2-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 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 1/2 hour.
- the ammonium salt of 2-(4-chlorophenyl)-a-methyl-5-benzoxazolylacetic 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, initially, the free acid, 2-(4-chlorophenyl)-a-methyl-5-benzoxazolylacetic acid as Form 1 which then underwent thermal conversion to Form II. 29.65 kg of purified free acid were obtained assayed at about 95 percent purity. The presence of Form II was demonstrated using X-ray powder diffraction and infra red analysis. Using the same drying system, the following times and temperatures were found to give 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.
- Tablets containing Benoxaprofen Form II were prepared using the following ingredients :
- 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 weekl cycling programme adopted was that specified below : This test is designed to mimic actual storage conditions. After two years the benoxaprofen was analysed and it was found (by analysis) that no less than 20% by weight of Form I had undergone polymorphic transformation to Form II. This experiment clearly illustrates the metastable nature of Form I.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (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)
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 true EP0000276A1 (fr) | 1979-01-10 |
EP0000276B1 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) | DE2828074A1 (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 (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7531564B2 (en) | 2001-12-05 | 2009-05-12 | Wyeth | Substituted benzoxazoles as estrogenic agents |
DE102022117931A1 (de) | 2022-07-18 | 2024-01-18 | HUECK System GmbH & Co. KG | Profilanordnung mit wärmedämmung |
Families Citing this family (7)
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 |
WO2021116820A1 (fr) * | 2019-12-10 | 2021-06-17 | Aurobindo Pharma Limited | Procédé amélioré pour la préparation de benoxaprofène |
US11981645B1 (en) | 2023-10-10 | 2024-05-14 | King Faisal University | N′-(2-naphthoyloxy)-2-(benzo[d]oxazol-2-yl)acetimidamide as antimicrobial compound |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7307018A (fr) * | 1972-05-18 | 1973-11-20 | ||
DE2450053A1 (de) * | 1973-10-23 | 1975-04-24 | Lilly Industries Ltd | 1,2-benzisoxazolderivate, verfahren zu ihrer herstellung und ihre verwendung in pharmazeutischen zubereitungen |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4087437A (en) * | 1976-09-07 | 1978-05-02 | Eli Lilly And Company | 2-Phenyl-5-benzoxazolylalkanoic acid purification process |
-
1977
- 1977-06-28 GB GB26907/77A patent/GB1590587A/en not_active Expired
-
1978
- 1978-06-26 NZ NZ187674A patent/NZ187674A/xx unknown
- 1978-06-26 DK DK287578A patent/DK145419C/da not_active IP Right Cessation
- 1978-06-26 CH CH691778A patent/CH631449A5/fr not_active IP Right Cessation
- 1978-06-27 AU AU37501/78A patent/AU518403B2/en not_active Expired
- 1978-06-27 EP EP78300082A patent/EP0000276B1/fr not_active Expired
- 1978-06-27 DE DE19782828074 patent/DE2828074A1/de not_active Ceased
- 1978-06-27 FR FR7819091A patent/FR2396004A1/fr active Granted
- 1978-06-27 IL IL55015A patent/IL55015A/xx unknown
- 1978-06-27 IE IE1277/78A patent/IE47009B1/en not_active IP Right Cessation
- 1978-06-27 BE BE6046515A patent/BE868522A/fr not_active IP Right Cessation
- 1978-06-27 DE DE7878300082T patent/DE2862013D1/de not_active Expired
- 1978-06-27 ZA ZA00783660A patent/ZA783660B/xx unknown
- 1978-06-27 LU LU79879A patent/LU79879A1/xx unknown
- 1978-06-27 FI FI782043A patent/FI69453C/fi not_active IP Right Cessation
- 1978-06-27 JP JP7795178A patent/JPS5411224A/ja active Granted
- 1978-06-27 AT AT466178A patent/AT360008B/de not_active IP Right Cessation
- 1978-06-27 IT IT50048/78A patent/IT1105065B/it active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7307018A (fr) * | 1972-05-18 | 1973-11-20 | ||
DE2450053A1 (de) * | 1973-10-23 | 1975-04-24 | Lilly Industries Ltd | 1,2-benzisoxazolderivate, verfahren zu ihrer herstellung und ihre verwendung in pharmazeutischen zubereitungen |
Non-Patent Citations (1)
Title |
---|
JOURNAL OF MEDICINAL CHEMISTRY, 18 (1975), Pages 53-58. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7531564B2 (en) | 2001-12-05 | 2009-05-12 | Wyeth | Substituted benzoxazoles as estrogenic agents |
DE102022117931A1 (de) | 2022-07-18 | 2024-01-18 | HUECK System GmbH & Co. KG | Profilanordnung mit wärmedämmung |
EP4310289A1 (fr) | 2022-07-18 | 2024-01-24 | HUECK System GmbH & Co. KG | Ensemble profilé doté d'une isolation thermique |
Also Published As
Publication number | Publication date |
---|---|
DK287578A (da) | 1978-12-29 |
FI69453C (fi) | 1986-02-10 |
IE47009B1 (en) | 1983-11-30 |
AU3750178A (en) | 1980-01-03 |
JPS6231714B2 (fr) | 1987-07-09 |
AT360008B (de) | 1980-12-10 |
FR2396004A1 (fr) | 1979-01-26 |
EP0000276B1 (fr) | 1982-09-01 |
IT7850048A0 (it) | 1978-06-27 |
IE781277L (en) | 1978-12-28 |
ATA466178A (de) | 1980-05-15 |
FR2396004B1 (fr) | 1981-09-18 |
FI782043A (fi) | 1978-12-29 |
DE2828074A1 (de) | 1979-01-11 |
LU79879A1 (fr) | 1978-12-07 |
CH631449A5 (fr) | 1982-08-13 |
DK145419B (da) | 1982-11-15 |
DE2862013D1 (en) | 1982-10-28 |
GB1590587A (en) | 1981-06-03 |
AU518403B2 (en) | 1981-10-01 |
DK145419C (da) | 1983-04-18 |
FI69453B (fi) | 1985-10-31 |
IL55015A (en) | 1981-11-30 |
IL55015A0 (en) | 1978-08-31 |
IT1105065B (it) | 1985-10-28 |
NZ187674A (en) | 1980-11-14 |
ZA783660B (en) | 1979-06-27 |
JPS5411224A (en) | 1979-01-27 |
BE868522A (fr) | 1978-12-27 |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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