EP0000276B1 - A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form - Google Patents
A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form Download PDFInfo
- 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
- Authority
- EP
- European Patent Office
- Prior art keywords
- benoxaprofen
- bands
- novel
- preparing
- pharmaceutical
- 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.)
- Expired
Links
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 title claims description 61
- 229960005430 benoxaprofen Drugs 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 150000003863 ammonium salts Chemical class 0.000 claims description 11
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000002329 infrared spectrum Methods 0.000 claims description 3
- 229910000570 Cupronickel Inorganic materials 0.000 claims description 2
- YOCUPQPZWBBYIX-UHFFFAOYSA-N copper nickel Chemical compound [Ni].[Cu] YOCUPQPZWBBYIX-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 description 9
- 239000002002 slurry Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HRYFKWATXKFOBY-UHFFFAOYSA-N 2-(1,3-benzoxazol-5-yl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C2OC=NC2=C1 HRYFKWATXKFOBY-UHFFFAOYSA-N 0.000 description 1
- RBGOLZYAUJDSGL-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanenitrile Chemical compound N=1C2=CC(C(C#N)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 RBGOLZYAUJDSGL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012612 commercial material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 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
- 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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB26907/77A GB1590587A (en) | 1977-06-28 | 1977-06-28 | Benoxaprofen |
| GB2690777 | 1977-06-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000276A1 EP0000276A1 (en) | 1979-01-10 |
| EP0000276B1 true EP0000276B1 (en) | 1982-09-01 |
Family
ID=10251100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78300082A Expired EP0000276B1 (en) | 1977-06-28 | 1978-06-27 | A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0000276B1 (cs) |
| JP (1) | JPS5411224A (cs) |
| AT (1) | AT360008B (cs) |
| AU (1) | AU518403B2 (cs) |
| BE (1) | BE868522A (cs) |
| CH (1) | CH631449A5 (cs) |
| DE (2) | DE2862013D1 (cs) |
| DK (1) | DK145419C (cs) |
| FI (1) | FI69453C (cs) |
| FR (1) | FR2396004A1 (cs) |
| GB (1) | GB1590587A (cs) |
| IE (1) | IE47009B1 (cs) |
| IL (1) | IL55015A (cs) |
| IT (1) | IT1105065B (cs) |
| LU (1) | LU79879A1 (cs) |
| NZ (1) | NZ187674A (cs) |
| ZA (1) | ZA783660B (cs) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021116820A1 (en) * | 2019-12-10 | 2021-06-17 | Aurobindo Pharma Limited | An improved process for the preparation of benoxaprofen |
Families Citing this family (8)
| 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)
| 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 |
-
1977
- 1977-06-28 GB GB26907/77A patent/GB1590587A/en not_active Expired
-
1978
- 1978-06-26 CH CH691778A patent/CH631449A5/fr not_active IP Right Cessation
- 1978-06-26 DK DK287578A patent/DK145419C/da not_active IP Right Cessation
- 1978-06-26 NZ NZ187674A patent/NZ187674A/xx unknown
- 1978-06-27 ZA ZA00783660A patent/ZA783660B/xx unknown
- 1978-06-27 EP EP78300082A patent/EP0000276B1/en not_active Expired
- 1978-06-27 AT AT466178A patent/AT360008B/de not_active IP Right Cessation
- 1978-06-27 DE DE7878300082T patent/DE2862013D1/de not_active Expired
- 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 FI FI782043A patent/FI69453C/fi not_active IP Right Cessation
- 1978-06-27 IT IT50048/78A patent/IT1105065B/it active
- 1978-06-27 FR FR7819091A patent/FR2396004A1/fr active Granted
- 1978-06-27 DE DE19782828074 patent/DE2828074A1/de not_active Ceased
- 1978-06-27 LU LU79879A patent/LU79879A1/xx unknown
- 1978-06-27 AU AU37501/78A patent/AU518403B2/en not_active Expired
- 1978-06-27 JP JP7795178A patent/JPS5411224A/ja active Granted
- 1978-06-27 BE BE6046515A patent/BE868522A/xx not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021116820A1 (en) * | 2019-12-10 | 2021-06-17 | Aurobindo Pharma Limited | An improved process for the preparation of benoxaprofen |
Also Published As
| Publication number | Publication date |
|---|---|
| DK145419C (da) | 1983-04-18 |
| DE2828074A1 (de) | 1979-01-11 |
| FR2396004A1 (fr) | 1979-01-26 |
| NZ187674A (en) | 1980-11-14 |
| ZA783660B (en) | 1979-06-27 |
| CH631449A5 (fr) | 1982-08-13 |
| ATA466178A (de) | 1980-05-15 |
| FI69453B (fi) | 1985-10-31 |
| FI782043A7 (fi) | 1978-12-29 |
| IL55015A0 (en) | 1978-08-31 |
| DK287578A (da) | 1978-12-29 |
| EP0000276A1 (en) | 1979-01-10 |
| AT360008B (de) | 1980-12-10 |
| DE2862013D1 (en) | 1982-10-28 |
| DK145419B (da) | 1982-11-15 |
| FI69453C (fi) | 1986-02-10 |
| JPS5411224A (en) | 1979-01-27 |
| LU79879A1 (cs) | 1978-12-07 |
| GB1590587A (en) | 1981-06-03 |
| IE781277L (en) | 1978-12-28 |
| FR2396004B1 (cs) | 1981-09-18 |
| AU3750178A (en) | 1980-01-03 |
| JPS6231714B2 (cs) | 1987-07-09 |
| IE47009B1 (en) | 1983-11-30 |
| IT1105065B (it) | 1985-10-28 |
| IT7850048A0 (it) | 1978-06-27 |
| IL55015A (en) | 1981-11-30 |
| BE868522A (fr) | 1978-12-27 |
| AU518403B2 (en) | 1981-10-01 |
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