GB1590587A - Benoxaprofen - Google Patents
Benoxaprofen Download PDFInfo
- Publication number
- GB1590587A GB1590587A GB26907/77A GB2690777A GB1590587A GB 1590587 A GB1590587 A GB 1590587A GB 26907/77 A GB26907/77 A GB 26907/77A GB 2690777 A GB2690777 A GB 2690777A GB 1590587 A GB1590587 A GB 1590587A
- Authority
- GB
- United Kingdom
- Prior art keywords
- benoxaprofen
- pharmaceutical formulation
- surrey
- ammonium salt
- preparing
- 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
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]
Description
PATENT SPECIFICATION ( 11) 1 590 587
( 21) Application No 26907/77 ( 22) Filed 28 Jun 1977 ( 19) Ug ( 23) Complete Specification Filed 31 May 19787 ( 44) Complete Specification Published 3 Jun 1981 / > ( 51) INT CL 3 C 07 D 263/56 / A 61 K 31/42 E X ( 52) Index at Acceptance C 2 C 1372 213 220 22 Y 246 255 25 Y 292 29 Y 303 313 31 Y 338 366 367 37 X 490 628 658 802 80 Y AA BD ( 72) Inventors: ROY SHERLOCK TERENCE ALAN HICKS ( 54) IMPROVEMENTS IN OR RELATING TO BENOXAPROFEN ( 71) We, LILLY INDUSTRIES LIMITED, a British Company of Lilly House, Hanover Square, London W 1 R OPA formerly of Henrietta House, Henrietta Place, London, W 1, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in
and by the following statement: 5
This invention relates to a novel polymorphic form of a pharmacologically active substance and to pharmaceutical formulations containing the novel polymorph.
The compound 2-( 4-chlorophenyl)-a-methyl-5-benzoxazolylacetic acid, hereinafter referred to by its generic name "benoxaprofen" is described in United Kingdom Patent Specification No 1,435,721 and in an article in the Journal of Medicinal Chemistry, 18, 53 10 ( 1975) as a potent anti-inflammatory agent, and is presently undergoing clinical trial.
Both the patent specification and the article are silent as regards polymorphic properties of benoxaprofen However, the laboratory procedures described in those publications result in formation of the kinetically preferred polymorphic form, hereinafter referred to as "Form I", of benoxaprofen However, this kinetically favoured polymorph is not the 15 thermodynamically stable form, which is hereinafter referred to as "Form II", and therefore tends to undergo polymorphic transformation on storage For instance, random cycling experiments carried out at temperatures between 4 and 370 C have shown 20 % transformation of Form I to Form II after two years When one considers that pharmaceutical formulations containing drugs of this type would generally be expected to 20 have a shelf life of the order of five years, it can be readily appreciated that the metastable nature of Form I presents serious problems with respect to commercially viable compositions such as tablets, creams and suspensions For a discussion of some of the problems associated with the utilisation of metastable forms of drugs in pharmaceutical formulations reference may be made to the review article in Journal of Pharmaceutical 25 Sciences, 58, 8, 911 ( 1969).
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.
2 1 590 587 2 According to the present invention there is provided a polymorphic form of benoxaprofen, crystals of which have the following powder diffraction pattern using filtered copper-nickel radiation at k= 1 5405.
"d" in A 1/10 5 11.77 10 8.06 10 7.07 70 5 67 100 10 5.30 10 5.06 20 4.79 10 4.41 50 4 17 80 15 3.93 05 3.65 30 3.56 90 3.24 60 3 09 40 20 3.03 15 2.97 15 2.81 05 2.75 05 2 66 05 25 2.57 05 2.37 10 2.29 05 2.15 05 2 04 15 30 1.98 20 1.91 05 1.78 02 Form II, characterised as above, can also be distinguished from Form I by its infra red 35 spectrum Using a Perkin Elmer 297 spectrophotometer with benoxaprofen homogeneously dispersed in a potassium bromide disc, the following differences can be observed:1 Form I exhibits a sharp, medium intensity band at 880 cm'1 whereas Form II exhibits a similar band at 885 cm.
2 In the region of 1200 1330 cm-' both forms show a similar positioning of bands, but the 40 intensities differ In Form I the bands at 1220 and 1250 cm-1 are considerably more intense than the others, whilst in Form II all bands are of similar intensity.
3 The strong band near 1700 cm>' is considerably sharper for Form I than for Form II.
Infra red analysis, which will be the usual method of assay of commerical material, is sensitive enough to detect as little as 10 % by weight of Form I in batches of Form II 45 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.
Accordingly, in a second aspect of the invention thereis provided Form II contaminated with less than 10 % by weight of Form I 50 According to a further aspect of the invention there is provided a pharmaceutical formulation comprising as an active material Form II associated with a pharmaceuticallyacceptable 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 55 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 The higher the temperature used the faster will be the polymorphic transformation from Form I to Form II Alternatively, Form II may be prepared by slow and controlled crystallisation from solutions of benoxaprofen in 60 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 4,087,437 According to one aspect of this procedure, benoxaprofen ammonium salt is isolated directly from the hydrolysis of 65 1 590 587 1 590 587 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 5 Alternatively, 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 If the purified acid thus produced is substantially insoluble in the solvent used to slurry the ammonium salt 10 (n-octane for example), benoxaprofen Form II will be obtained as from heating the salt in the absence of a solvent If benoxaprofen is soluble in the solvent used to slurry the ammonium salt, (n-butyl acetate for example) a recrystallized product will be obtained.
With either type of solvent benoxaprofen can be separated from the solvent by decantation or filtration If benoxaprofen is soluble in the solvent employed, the solution is ordinarily 15 concentrated and/or chilled to increase crystallization and further crystals are obtained from the mother liquor.
The following non-limitative Examples will serve to illustrate the nature and advantages of the invention.
20 Example 1
The process described in Method D, page 55 from Journal of Medicinal Chemistry, 18, ( 1975) was repeated exactly The recrystallisation procedure adopted was conventional, i e.
the solution of benoxaprofen in ethanol was formed by warming on a steam bath and cooling of the thus-formed solution was effected using an ice-bath 25 Infra-red analysis and X-ray powder diffraction both showed that exclusive formation of Form I had occurred.
Example 2
41 kg of 2-( 4-chlorophenyl)-a-methyl-5-benzoxazolylacetonitrile were hydrolyzed in 12 N 30 aqueous hydrochloric acid by being stirred at 80 'C for about two hours The reaction mixture was cooled to about 40 'C and then poured slowly with vigorous stirring into cold water The solid precipitate 2-( 4-chlorophenyl)-ct-methyl-5benzoxazolylacetic acid thus prepared was collected by filtration and the filter cake washed with water until the washings no longer gave an acidic reaction to litmus The filter cake was dried at 70-800 C; yield = 40 35 kg ( 77 percent purity) The filter cake was then dissolved in 48 3 litres of dimethylformamide at 550 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 8 percent aqueous ammonium hydroxide added very slowly to the filtrate maintained at about 350 C over a period of about 1/2 hour During the addition of the aqueous ammonium hydroxide, the 40 ammonium salt of 2-( 4-chlorophenyl)-a-methyl-5-benzoxazolylacetic acid slowly precipitated yielding a slurry After the addition of the ammonium hydroxide had been completed, the p H of the slurry was checked and found to be about 9 The slurry was next chilled in an ice-water mixture to about 00 C and the precipitated ammonium salt separated by filtration.
The filter cake was washed with cold acetone ( 00 C) and the washed filter cake dried at 45 1250 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)-amethyl-5benzoxazolylacetic acid as Form I 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 50 analysis Using the same drying system, the following times and temperatures were found to give Form 11 ( 97 % or higher purity) 6 hours at 950 C, 2 5 hours at 1250 C, 1 5 hours at 140 'C, 0.5 hours at 155 C.
Example 3 55
Benoxaprofen ( 892 g) Form I was suspended in n-butyl acetate ( 9 8 litres) and the stirred suspension heated to the reflux temperature of the solvent to form a solution The temperature of the solution was then slowly reduced ( 10 every hour) until room temperature was reached.
The crystals of benoxaprofen thus produced were filtered off, washed with ethanol ( 892 60 ml) and dried in vacuo at 80 C Yield 760 g.
The infra red spectrum and X-ray powder diffraction of the crystals shows that pure form II had been obtained.
4 1 590 587 4 Example 4
Tablets containing Benoxaprofen Form II were prepared using the following ingredients:
Weight (mg) 5 Form II 100 Starch 55 1 Polyvinylpyrrolidone 8 25 Magnesium Stearate 1 65 10 The Form II and the starch were admixed and granulated with the polyvinylpyrrolidone as a % 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 15 compressed into tablets.
Tablets thus prepared were stored at 4, 25 and 40 C for two years No detioration in the physical characteristics of the tablets or in their appearance was noted over this period of time.
20 Example 5
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 25specified below: 25 25 Monday Tuesday Wednesday Thursday Friday Saturday Sunday 37 C 4 C 15 C 37 C 4 C 15 C 15 C This test is designed to mimic actual storage conditions After two years the 30 benoxaprofen was analysed and it was found (by infra-red 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.
Claims (1)
- WHAT WE CLAIM IS:-1 Benoxaprofen form II 35 2 Benoxaprofen Form II contaminated with less than 10 % by weight of Form I.3 A pharmaceutical formulation which contains as an active ingredient Benoxaprofen Form II as claimed in claim 1 or 2, associated with a pharmaceuticallyacceptable carrier therefor.4 A pharmaceutical formulation according to claim 3, in the form of a tablet 40 A method of preparing a pharmaceutical formulation which comprises admixing Benoxaprofen Form II as claimed in claim 1 or 2 with a pharmaceuticallyacceptable carrier therefor.6 A method of preparing Benoxaprofen Form II which comprises the slow and controlled crystallisation of Benoxaprofen from a solution in n-butyl acetate 45 7 The method of claim 6, substantially as hereinbefore described with reference to foregoing Example 3.P.G STRINGER, Chartered Patent Agent, 50 Erl Wood Manor, Windlesham, Surrey, England.Agent for the Applicants.Printed for Her Majesty's Stationery Office by Croydon Printing Company Limited, Croydon, Surrey, 1981.Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.1 590 587
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB26907/77A GB1590587A (en) | 1977-06-28 | 1977-06-28 | Benoxaprofen |
DK287578A DK145419C (en) | 1977-06-28 | 1978-06-26 | PROCEDURE FOR PREPARING A THERMODYNAMIC STABLE FORM (II) OF THE BENOXAPROFEN |
CH691778A CH631449A5 (en) | 1977-06-28 | 1978-06-26 | NEW CRYSTALLINE FORM OF THE ANTI-INFLAMMATORY AGENT: 2- (4-CHLOROPHENYL-ALPHA-METHYL-5-BENZOXAZOLYLACETIC ACID, PROCESS FOR ITS PREPARATION AND APPLICATION AS MEDICAMENTS. |
NZ187674A NZ187674A (en) | 1977-06-28 | 1978-06-26 | 2-(4-chlorophenyl)-methyl-5-benzoxazolylacetic acid and pharmaceutical compositions |
DE19782828074 DE2828074A1 (en) | 1977-06-28 | 1978-06-27 | FORM II OF 2- (4-CHLORPHENYL) - ALPHA-METHYL-5-BENZOXAZOLYL-ACETIC ACID, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PRODUCTS CONTAINING IT |
IT50048/78A IT1105065B (en) | 1977-06-28 | 1978-06-27 | IMPROVEMENT IN THE PRODUCTION PROCEDURES OF 2- (4-CHLORO-FENYL) -ALPHA-METHY-5-BENZONAZOLYLACETIC ACID |
IL55015A IL55015A (en) | 1977-06-28 | 1978-06-27 | Polymorphic form of benoxaprofen,its preparation and pharmaceutical compositions containing it |
BE6046515A BE868522A (en) | 1977-06-28 | 1978-06-27 | NEW CRYSTALLINE FORM OF ANTI-INFLAMMATORY AGENT: ACID 2 - (- 4-CHLOROPHENYL) -? - METHYL-5-BENZOXAZOLYLACETIC, PROCESS FOR ITS PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS |
AT466178A AT360008B (en) | 1977-06-28 | 1978-06-27 | METHOD FOR PRODUCING THE THERMOSTABLE FORM OF 2- (4-CHLORPHENYL) ALPHA-METHYL-5-BENZOXAZOLYL-ACETIC ACID |
LU79879A LU79879A1 (en) | 1977-06-28 | 1978-06-27 | |
AU37501/78A AU518403B2 (en) | 1977-06-28 | 1978-06-27 | Polymorphic form of benoxaprofen |
IE1277/78A IE47009B1 (en) | 1977-06-28 | 1978-06-27 | Improvements in or relating to benoxaprofen |
ZA00783660A ZA783660B (en) | 1977-06-28 | 1978-06-27 | Improvements in or relating to benoxaprofen |
FI782043A FI69453C (en) | 1977-06-28 | 1978-06-27 | SAETT ATT FRAMSTAELLA IN NY POLYMORF FORM AV THERAPEUTIC ANVAENDBAR 2- (4-CHLOROPHENYL) -ALPHATE-METHYL-5-BENZOZAZOLYL ETH |
EP78300082A 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 |
DE7878300082T DE2862013D1 (en) | 1977-06-28 | 1978-06-27 | A novel crystalline form of benoxaprofen, methods of preparation thereof and pharmaceutical formulations containing said novel form |
JP7795178A JPS5411224A (en) | 1977-06-28 | 1978-06-27 | Improvement of benoxaprophene |
FR7819091A FR2396004A1 (en) | 1977-06-28 | 1978-06-27 | NEW CRYSTALLINE FORM OF ANTI-INFLAMMATORY AGENT: 2- (4-CHLOROPHENYL) -A-METHYL-5-BENZOXAZOLYLACETIC ACID, PROCESS FOR ITS PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS |
DK319181A DK145697C (en) | 1977-06-28 | 1981-07-16 | PROCEDURE FOR PREPARING A THERMODYNAMIC STABLE FORM (II) OF THE BENOXAPROFEN |
FI831930A FI69454C (en) | 1977-06-28 | 1983-05-30 | SAETT ATT FRAMSTAELLA EN THERMODYNAMIC STABILIZED POLYMORF FORM OF THERAPEUTIC ANVAENDBAR 2- (4-CHLOROPHENYL) -ALPHATE-METHYL-5-BENZOZAZOLYL ACETY |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB26907/77A GB1590587A (en) | 1977-06-28 | 1977-06-28 | Benoxaprofen |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1590587A true GB1590587A (en) | 1981-06-03 |
Family
ID=10251100
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB26907/77A Expired GB1590587A (en) | 1977-06-28 | 1977-06-28 | Benoxaprofen |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0000276B1 (en) |
JP (1) | JPS5411224A (en) |
AT (1) | AT360008B (en) |
AU (1) | AU518403B2 (en) |
BE (1) | BE868522A (en) |
CH (1) | CH631449A5 (en) |
DE (2) | DE2828074A1 (en) |
DK (1) | DK145419C (en) |
FI (1) | FI69453C (en) |
FR (1) | FR2396004A1 (en) |
GB (1) | GB1590587A (en) |
IE (1) | IE47009B1 (en) |
IL (1) | IL55015A (en) |
IT (1) | IT1105065B (en) |
LU (1) | LU79879A1 (en) |
NZ (1) | NZ187674A (en) |
ZA (1) | ZA783660B (en) |
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 (en) * | 1978-08-04 | 1985-09-18 | Ravizza Spa | PROCESS FOR THE PREPARATION OF PROPIONIC BENZOXAZOLYL ACID DERIVATIVES |
IT1157295B (en) * | 1982-07-19 | 1987-02-11 | Ravizza Spa | PROCESS PERFECTED FOR THE PREPARATION OF DERIVATIVES OF BENZOXAZOLYL PROPIONIC ACID |
UA83620C2 (en) | 2001-12-05 | 2008-08-11 | Уайт | Substituted benzoxazoles and analogues as estrogenic agents |
WO2021116820A1 (en) * | 2019-12-10 | 2021-06-17 | Aurobindo Pharma Limited | An improved process for the preparation of benoxaprofen |
DE102022117931A1 (en) | 2022-07-18 | 2024-01-18 | HUECK System GmbH & Co. KG | PROFILE ARRANGEMENT WITH THERMAL INSULATION |
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 DK DK287578A patent/DK145419C/en not_active IP Right Cessation
- 1978-06-26 NZ NZ187674A patent/NZ187674A/en unknown
- 1978-06-26 CH CH691778A patent/CH631449A5/en not_active IP Right Cessation
- 1978-06-27 DE DE19782828074 patent/DE2828074A1/en not_active Ceased
- 1978-06-27 AT AT466178A patent/AT360008B/en not_active IP Right Cessation
- 1978-06-27 DE DE7878300082T patent/DE2862013D1/en not_active Expired
- 1978-06-27 ZA ZA00783660A patent/ZA783660B/en unknown
- 1978-06-27 EP EP78300082A patent/EP0000276B1/en not_active Expired
- 1978-06-27 IT IT50048/78A patent/IT1105065B/en active
- 1978-06-27 IE IE1277/78A patent/IE47009B1/en not_active IP Right Cessation
- 1978-06-27 JP JP7795178A patent/JPS5411224A/en active Granted
- 1978-06-27 BE BE6046515A patent/BE868522A/en not_active IP Right Cessation
- 1978-06-27 FI FI782043A patent/FI69453C/en not_active IP Right Cessation
- 1978-06-27 LU LU79879A patent/LU79879A1/xx unknown
- 1978-06-27 FR FR7819091A patent/FR2396004A1/en active Granted
- 1978-06-27 AU AU37501/78A patent/AU518403B2/en not_active Expired
- 1978-06-27 IL IL55015A patent/IL55015A/en unknown
Also Published As
Publication number | Publication date |
---|---|
DK287578A (en) | 1978-12-29 |
DK145419C (en) | 1983-04-18 |
BE868522A (en) | 1978-12-27 |
FR2396004A1 (en) | 1979-01-26 |
IT7850048A0 (en) | 1978-06-27 |
EP0000276B1 (en) | 1982-09-01 |
AT360008B (en) | 1980-12-10 |
JPS6231714B2 (en) | 1987-07-09 |
IE781277L (en) | 1978-12-28 |
LU79879A1 (en) | 1978-12-07 |
IT1105065B (en) | 1985-10-28 |
FI782043A (en) | 1978-12-29 |
DE2828074A1 (en) | 1979-01-11 |
JPS5411224A (en) | 1979-01-27 |
IE47009B1 (en) | 1983-11-30 |
IL55015A (en) | 1981-11-30 |
IL55015A0 (en) | 1978-08-31 |
CH631449A5 (en) | 1982-08-13 |
FI69453B (en) | 1985-10-31 |
EP0000276A1 (en) | 1979-01-10 |
AU518403B2 (en) | 1981-10-01 |
AU3750178A (en) | 1980-01-03 |
NZ187674A (en) | 1980-11-14 |
ZA783660B (en) | 1979-06-27 |
DK145419B (en) | 1982-11-15 |
DE2862013D1 (en) | 1982-10-28 |
FI69453C (en) | 1986-02-10 |
FR2396004B1 (en) | 1981-09-18 |
ATA466178A (en) | 1980-05-15 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920531 |