GB2052506A - Process for preparing a crystalline form of flunisolide - Google Patents
Process for preparing a crystalline form of flunisolide Download PDFInfo
- Publication number
- GB2052506A GB2052506A GB8016683A GB8016683A GB2052506A GB 2052506 A GB2052506 A GB 2052506A GB 8016683 A GB8016683 A GB 8016683A GB 8016683 A GB8016683 A GB 8016683A GB 2052506 A GB2052506 A GB 2052506A
- Authority
- GB
- United Kingdom
- Prior art keywords
- flunisolide
- solution
- alkanol
- water
- diffraction pattern
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- 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]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A unique crystalline form of flunisolide is prepared by crystallizing flunisolide from a solution thereof in an alkanol of three or four carbon atoms, e.g. n-butanol, containing 0.2 to 5%, preferably 1.0 to 4.0% by volume water.
Description
SPECIFICATION
Process for preparing a crystalline modification of flunisolide
This invention relates to a process for making a
unique crystalline form of flunisolide (hereafter
Form A).
Flunisolide is the United States adopted name for 6a-fluoro-1 1,21-dihydrnxy-1 6a,1 7a- isopropylidenedioxypregna-1 ,4-diene-3,20-dione.
The class of compounds to which flunisolide belongs and procedures for preparing them are described in United States Patent 3,126,375 to
Ringold et al. These compounds exhibit antiinflammatory and anti-pyretic activity and have primary utility in the treatment of topical inflammation. Fiunisolide may also be formulated with pharmaceutically acceptable aerosol propellants and used to treat respiratory conditions such as asthma, allergic rhinitis, etc. in mammals (see, for example, Belgian Patent No.
842,192). One particular polymorphic form (Form
A, a hemihydrate) of flunisolide has been found to be particularly stable in the presence of aerosol propellant formulations and therefore is preferred (see the aforementioned Belgian Patent No.
842,192). However, because of the ability of flunisolide to form various polymorphic forms as well as to form crystal habits which include some of the solvents from which the product is crystallized, a process must be employed which reproducibly gives the desired Form A of flunisolide.
In U.S. Patent 3,126,375 to Ringold et al.
solvents used for crystallization of the family of steroids of which flunisolide is a member include such solvents as ethyl acetate and methanol.
However, when these solvents are used to recrystallize flunisolide it is found that generally flunisolide forms a clathrate, solvate, or related solvent inclusion complex with these solvents.
Such crystal forms of flunisolide are unacceptable because of the uniformity required for a pharmaceutically acceptable aerosol formulation.
In Belgian Patent No. 842,192 a process is disclosed for preparing Form A of flunisolide.
However, that particular process employs halogenated hydrocarbons which have some undesirable properties.
It has now been found that Form A of flunisolide (a hemihydrate) can be reproducibly obtained by the process of this invention. The process comprises crystallizing flunisolide from an aqueous solution of an alkanol of three or four carbon atoms. The crystals formed in this manner reproducibly exhibit Form A, crystalline flunisolide.
This is surprising, especially in view of the fact that if one recrystallizes flunisolide from an aqueous solution of methanol or ethanol one does not obtain Form A.
The unique crystalline form of flunisolide which is prepared by the process of this invention is a heinihydrate, crystalline flunisolide, 6a-fluoro- 11p,21-dihydroxy-16c2,17a- isopropylidenedioxypregna- ,4-diene-3,20-dione and is referred to herein as Form A. The crystalline structure has a powder X-ray diffraction pattern as indicated in Table A below.
TABLE A
d l/11 8
A % deg.
10.04 50 4.4
9.82 60 4.5
9.30 80 4.8
7.69 50 5.8
6.91 50 6.4
6.32 10 7.0
5.98 90 7.4
5.53 100 8.0
5.21 60 8.5
5.06 60 8.8
4,79 10 9.3
4.55 70 9.8
4.33 1 10.3
4.13 10 10.8
3.95 10 11.3
3.86 5b 11.5
3.70 5 12.0
3.63 10 12.3
3.36 1 13.3
3.30 2 13.5
3.21 2 13.9
3.03 1 14.8
2.88 2 15.5
2.67 2b 16.8
2.63 1 17.0
2.60 1 17.3
2.56 1 17.5
2.40 3 18.8
2.31 1 19.5
TABLE A (continued)
d l/11 0 A % deg.
2.28 1 19.8
2.13 1 21.3
2.10 1 21.5
1.97 1 23.0
1.88 2 24.3 b = broad line due to failure to resolve two closely
spaced lines.
A general discussion of the theory and definitions as well as the general procedure of Xray diffractometry is set forth in the monograph at pages 902-904 of the National Formulary, XIII.
The above X-ray diffraction pattern was obtained in accordance with the method described in Belgian Patent No. 842,192.
Form A of flunisolide is further characterized by the presence of 2.0 + 0.2 percent (%) by weight water. Because the calculated stoichiometric value of the percentage of water by weight for ahemihydrate of flunisolide is 2.03%, it appears that Form A is a hemihydrate.
Analysis of Form A for water content is done by any suitable analytical method. Generally analysis is done using Karl Fischer reagent. The Karl
Fischer analysis for water may be performed according to the original method set forth in
Angewandte Chemie, 48, 394 (1935). Preferably, however, the analysis is performed using
Photovolt Corporation's automatic analyzer,
Aquatest IV. The Aquatest IV is a coulometric titrator which incorporates microprocessor control and is based on the specific and quantitative reaction of water with Karl Fischer reagent. The instrument is unique in that the reagent is generated electronically which eliminates the need for standardization or caiibration. The accuracy of the instrument is within j 10 micrograms (mcg) or 1% whichever is greater.For determination of water in flunisolide Form A, where the sample sizes chosen for the determinations are between 35 mg and 75 mg and contain between 700 mcg and 1 500 mcg of water, the accuracy is within +0.03% of the amount of water determined in mcg.
The microprocessor control serves to distinguish between the titration of water which is in the sample and any reaction of the Karl Fischer reagent with other entities such as aldehydes or ketones. The Aquatest IV is operated as described in the instruction manual published by Photovolt
Corporation in July 1978 and by Paper No. 260 presented at the Pittsburg Conference on
Analytical Chemistry and Applied Spectroscopy in
February of 1978 by K. A. Lindblom. The address of Photovolt Corporation is 111 5 Broadway, New
York, New York 10010.
In the process of this invention it is important that the equipment that is used for the crystallization of flunisolide is completely clean. If there is another polymorphic form of flunisolide present in the flask or container in which the crystallization takes place the desired Form A may be contaminated with another phase which is formed simultaneously due to the crystailization which is directed by the existing crystals of flunisolide. Thus, before performing the process of the invention it is wise to wash all equipment thoroughly with the alkanol to be used, e.g.
aqueous n-butanol, to assure that any extraneous flunisolide of a different crystal form is completely removed from the equipment.
As pointed out previously, the process of the invention comprises crystallizing flunisolide from an aqueous solution of an alkanol of three or four carbon atoms. Alkanols of 3 or 4 carbon atoms include, for example, isopropyl alcohol, npropanol, n-butanol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol. N-butanol is preferred.
The alkanol is aqueous, that is, it contains about 0.2 to 5% water by volume, and preferably contains 1 to 4% water by volume. With nbutanol, about 2.3% by volume is used.
The fiunisolide solution can be obtained in several ways. Any polymorphic form of flunisolide can be added to the alkanol or the alkanol can be added to the crystalline form and agitated until the flunisolide is entirely in solution. Thereafter, the desired amount of water can be added. l However, for the preparation of the solution, aqueous alkanol also can be used. In order to speed the process of solution the alkanol can be heated to a temperature of 750C or more, up to its boiling point (e.g. for n-butanol 11 70C). Alternatively, the alkanol can be added to an existing solution of flunisolide in another solvent with a lower boiling point than the alkanol.For example, n-butanol can be added to a solution of flunisolide in methylene chloride and the methylene chloride distilled off while n-butanol becomes the solvent for flunisolide. This is done through replacement distillation. It it important, of course, to use sufficient alkanol to keep the flunisolide in solution. Thereafter, water is added. Thus, the concentration of flunisolide will vary with the alkanol used. It has been found that about 50 grams of flunisolide will dissolve at 800C in 250 milliliters (ml) of n-butanol containing 2% v/v water and crystallize from solution at about 350C and give the new crystalline Form A.
Once a solution of flunisolide in the alkanol is obtained, the crystallization of the flunisolide is effected, preferably at a temperature of less than about 750C. For example, this can be done by allowing an n-butanol solution to slowly cool, e.g., at a rate of 1 every 30 seconds to about 10 minutes. The initial temperature of the aqueous solution can be anywhere from about 300C to about the boiling point of the alkanol.
Although the desired Form A of flunisolide is obtained by allowing the crystallization through cooling alone, such a process may not always be economically advantageous because of the large amount of flunisolide remaining in solution. On a small scale, a suitable alkane solvent (in which flunisolide has little solubility) may be added to the alkanol solution to force the flunisolide from solution. The alkane solvent is preferably n-hexane or n-heptane. Generally the volume of n-hexane or n-heptane which is added is about twice to about five times the volume of the alkanol solution, and is added slowly to the alkanol solution containing about 50 9 of fiunisolide over an extended period of time, e.g. about 10 minutes to 4 hours or more, depending on the volumes of the solvents involved.For example, 750 ml of n-hexane may be added to about 250 ml of an aqueous n-butanol flunisolide solution over an hour. The alkane solvent may be at the same temperature as the nbutanol solution, or less, but preferably is at ambient temperature, i.e. about 20-250C to speed the crystallization.
Once the steroid crystals are obtained, they are dried by means known in the art such as vacuum drying to remove any solvent. This may be done for a period of 2 hours to several days.
The uunique crystalline structure of flunisolide having the X-ray diffraction pattern of Table A can be distinguished from other polymorphic forms of flunisolide using, i.a., analysis by X-ray powder diffraction, differential scanning calorimetry, polarized light microscopy, water analysis and hot stage microscopy.
The following examples are given to further set forth specific, representative conditions for the process of the invention but are not to be interpreted as limiting the scope of the claims appended hereto.
EXAMPLE 1
Fifty (50) grams (g) of damp flunisolide (containing about 1% by weight water) are placed in a 1 liter Erlenmeyer flask provided with magnetic stirring, and 250 milliliters (ml) of nbutanol containing about 0.1% by volume water is added. The mixture is heated to 700 until complete dissolution is achieved and then the solution is left to cool slowly at approximately 1 degree per minute. At about 350C crystallization becomes apparent and at 300C n-heptane is slowly added over a period of about 1 hour until the total volume of the mixture is 1 liter. After stirring for a further hour at ambient temperature, the product is filtered, washed several times with n-heptane and air dried.The material is then dried in a vacuum oven at 500C for three days to yield 45 grams of flunisolide having a powder X-ray diffraction pattern set forth in Table A.
Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV gives 1.93% water.
EXAMPLE 2
One hundred (100) grams of flunisolide are placed in a 500 ml Erlenmeyer flask provided with magnetic stirring, and 1 96 ml analytical grade nbutanol and 4 ml distilled water are added. The mixture is heated with stirring to 950C until
complete dissolution is achieved, then cooled with
stirring. At about 700 crystallization becomes
apparent. The resulting slurry is cooled to room
temperature and stirred overnight. The product is
then filtered and air-dried, yielding 85 g flunisolide
having the powder X-ray diffraction pattern set forth in Table A.
Analysis of the resulting crystals using Karl
Fischer reagent in Photovolt's Aquatest gives
1.93% w/water.
EXAMPLE 3
Ten (10) grams of flunisolide are placed in a
50 ml Erlenmeyer flask provided with magnetic
stirring and 1 5 ml n-propanol plus 0.6 ml distilled water added. The mixture is heated with stirring to
900C until complete dissolution is achieved, then
cooled with stirring. Crystallization becomes apparent at about 600, and the resulting slurry is cooled with stirring to room temperature. After overnight stirring at room temperature, the product is filtered and air dried, giving 8.6 g flunisolide having the power X-ray diffraction pattern set forth in Table A.
Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV gives 2.08% w/water.
EXAMPLE 4
Ten (10) grams flunisolide are placed in a 50 ml
Erlenmeyer flask equipped with magnetic stirring and 20 ml isopropyl alcohol and 1 ml distilled water added. This mixture is heated to about 70 C until a clear solution is obtained, then cooled with stirring. Crystallization becomes evident at 50--600C. The resulting slurry is cooled to room temperature and stirred overnight. After standing for 6 days at room temperature, filtering, air drying, drying in vacuo at room temperature for 24 hours, 8.5 g of flunisolide is obtained having the powder X-ray diffraction pattern set forth in
Table A.
Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV gives 2.18% water.
EXAMPLE 5
Two (2) grams of flunisolide having the X-ray diffraction pattern set forth in Table A are added to a flask containing 10 ml of 95% ethanol at room temperature. The mixture was heated with stirring until all of the material was entirely dissolved. The resulting solution was then allowed to cool to room temperature while scratching the sides of the flask with a glass rod to induce crystallization.
The crystals obtained were analyzed using polarized light microscopy and were found to be different than the flunisolide used initially.
EXAMPLE 6
The procedure of Example 5 was repeated except that crystallization was induced by seeding with a small amount of flunisolide having the Xray diffraction pattern of Table A. The resulting crystals so obtained were analyzed using polarized light microscopy and were found to differ from the flunisolide used as seed crystals.
EXAMPLE 7
Fifty (50) grams of flunisolide were added to 600 ml methanol and heated to dissolve all the flunisolide, then allowed to cool. The volume of the resulting solution was reduced by half on a rotary evaporater, then the resulting slurry was filtered and crystalline flunisolide isolated. The filtrate was again evaporated down to approximately 60 ml volume, then filtered again as above. The resultant material was air dried, giving 26 gms of flunisolide which differs (as analyzed via X-ray diffractometry, differential scanning calorimetry, visual thermal analysis, and weight loss on heating of 2.6%) from that having the X-ray diffraction pattern set forth in Table A.
EXAMPLE 8
One hundred (100) mg flunisolide was dissolved in 20 ml absolute ethanol at approximately 70"0. The resulting solution was cooled to room temperature and allowed to evaporate over a three-day period. The resultant crystalline fiunisolide was collected, analyzed by
X-ray diffractometry, differential scanning calorimetry, visual thermal analysis, and weight loss on heating (4.5, 4.9%). The resulting crystalline flunisolide was found to differ from the crystalline flunisolide exhibiting the X-ray diffraction pattern of Table A.
EXAMPLE 9
Ten (10) grams flunisolide are placed in a 50 ml
Erlenmeyer flask equipped with magnetic stirring and 20 ml t-butyl alcohol and 1 ml distilled water added. This mixture is heated until a clear solution is obtained then cooled with stirring until crystallization becomes evident. The resulting slurry is cooled to room temperature and stirred overnight. The resulting mixture is filtered, air dried and dried in vacuo at room temperature for 24 hours to give flunisolide having the powder Xray diffraction pattern set forth in Table A.
Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV gives about 2% by weight water.
Claims (8)
1. A process for preparing a crystalline form of flunisolide which contains 2.0 + 0.2% by weight water and exhibits an X-ray diffraction pattern as set forth in Table A:
TABLE A
d 1/1i deg.
10.04 50 4.4
9.82 60 4.5
9.30 80 4.8
7.69 50 5.8
TABLE A (continued)
d l/11 0 A % deg.
6.91 50 6.4 6.32 10 7.0 5.98 90 7.4 5.53 100 8.0 5.21 60 8.5 5,06 60 8.8 4.79 10 9.3 4.55 70 9.8 4.33 1 10.3 4.13 10 10.8 3.95 10 11.3 3.86 5b 11.5 3.70 5 12.0 3.63 10 12.3 3.36 1 13.3 3.30 2 13.5 3.21 2 13.9 3.03 1 14.8 2.88 2 15.5 2.67 2b 16.8 2.63 1 17.0 2.60 1 17.3 2.56 1 17.5 2.40 3 18.8 2.31 1 19.5 2.28 1 19.8 2.13 1 21.3 2.10 1 21.5 1.97 1 23.0 1.88 2 24.3 which process comprises crystallizing said steroid from a solution of said steroid in a liquid alkanol of three or four carbon atoms containing 0.2 to 5% water by volume.
2. The process of Claim 1 wherein said solution contains 1 to 4% water by volume.
3. The process of Claim 1 or 2 wherein said alkanol is n-butanol.
4. The process of Claim 1 or 2 wherein said alkanol is isopropyl alcohol or n-propyl alcohol.
5. The process of Claim 1 or 2 wherein said alkanol solution is allowed to cool from a temperature above 750C to a temperature below 750C at which crystallization takes place.
6. The process of one of the preceding claims wherein said solution is cooled to a temperature below 300C.
7. A crystalline form of flunisolide which contains 2.0 + 0.2% by weight water and exhibits an X-ray diffraction pattern as set forth in Table A, as follows:
TABLE A
d l/11 0 A % deg.
10.04 50 4.4
9.82 60 4.5
9.30 80 4.8
7.69 50 5.8
6.91 50 6.4
6.32 10 7.0
5.98 90 7.4
5.53 100 8.0
5.21 60 8.5
5.06 60 8.8
4.79 10 9.3
4.55 70 9.8
4.33 1 10.3
TABLE A (continued)
d l/11 0 A % deg.
4.13 10 10.8
3.95 10 11.3
3.86 5b 11.5
3.70 5 12.0
3.63 10 12.3
3.36 1 13.3
3.30 2 13.5
3.21 2 13.9
3.03 1 14.8
2.88 2 15.5
2.67 2b 16.8
2.63 1 17.0
2.60 1 17.3
2.56 1 17.5
2.40 3 18.8
2.31 1 19.5
2.28 1 19.8
2.13 1 21.3
2.10 1 21.5
1.97 1 23.0
1.88 2 24.3 obtained by a process of one of the preceding claims.
8. A process according to Claim 1 substantially as described herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4083079A | 1979-05-21 | 1979-05-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2052506A true GB2052506A (en) | 1981-01-28 |
| GB2052506B GB2052506B (en) | 1983-01-19 |
Family
ID=21913206
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8016683A Expired GB2052506B (en) | 1979-05-21 | 1980-05-20 | Process for preparing acrystalline form of flunisolide |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS55154997A (en) |
| AU (1) | AU532084B2 (en) |
| BE (1) | BE883381A (en) |
| CA (1) | CA1153761A (en) |
| CH (1) | CH643567A5 (en) |
| DE (1) | DE3019250C2 (en) |
| DK (1) | DK162530C (en) |
| FR (1) | FR2457303A1 (en) |
| GB (1) | GB2052506B (en) |
| HK (1) | HK40784A (en) |
| IL (1) | IL60128A (en) |
| IT (1) | IT1133092B (en) |
| MY (1) | MY8500694A (en) |
| NL (1) | NL189201C (en) |
| NZ (1) | NZ193778A (en) |
| SE (1) | SE431549B (en) |
| SG (1) | SG37585G (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1121513B (en) * | 1979-05-28 | 1986-04-02 | Chiesi Farma Spa | PROCESS FOR THE CONVERSION OF ANTI-INFLAMMATORY STEROID UMO IN A SUSCEPTIBLE FORM OF BEING ADMINISTERED AS AN AEROSOL |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX3864E (en) * | 1975-05-27 | 1981-08-26 | Syntex Corp | A PROCESS TO PREPARE THE CRYSTALLINE COMPOUND 6-FLUIRO-11B 21-DIHIROXI-16 17-ISOPROPILIDENDIOXIPREGNA-1 4-DIEN-3 20-DIONA |
-
1980
- 1980-05-20 JP JP6603580A patent/JPS55154997A/en active Granted
- 1980-05-20 NZ NZ193778A patent/NZ193778A/en unknown
- 1980-05-20 FR FR8011254A patent/FR2457303A1/en active Granted
- 1980-05-20 AU AU58566/80A patent/AU532084B2/en not_active Expired
- 1980-05-20 IL IL60128A patent/IL60128A/en unknown
- 1980-05-20 IT IT67791/80A patent/IT1133092B/en active Protection Beyond IP Right Term
- 1980-05-20 BE BE0/200678A patent/BE883381A/en not_active IP Right Cessation
- 1980-05-20 GB GB8016683A patent/GB2052506B/en not_active Expired
- 1980-05-20 CH CH393980A patent/CH643567A5/en not_active IP Right Cessation
- 1980-05-20 DK DK219280A patent/DK162530C/en not_active IP Right Cessation
- 1980-05-20 DE DE3019250A patent/DE3019250C2/en not_active Expired
- 1980-05-20 NL NLAANVRAGE8002902,A patent/NL189201C/en not_active IP Right Cessation
- 1980-05-20 SE SE8003761A patent/SE431549B/en not_active IP Right Cessation
- 1980-05-21 CA CA000352333A patent/CA1153761A/en not_active Expired
-
1984
- 1984-05-10 HK HK407/84A patent/HK40784A/en not_active IP Right Cessation
-
1985
- 1985-05-18 SG SG375/85A patent/SG37585G/en unknown
- 1985-12-30 MY MY694/85A patent/MY8500694A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6258360B2 (en) | 1987-12-05 |
| NZ193778A (en) | 1982-03-16 |
| IT1133092B (en) | 1986-07-09 |
| MY8500694A (en) | 1985-12-31 |
| JPS55154997A (en) | 1980-12-02 |
| DK219280A (en) | 1980-11-22 |
| AU532084B2 (en) | 1983-09-15 |
| HK40784A (en) | 1984-05-18 |
| GB2052506B (en) | 1983-01-19 |
| NL8002902A (en) | 1980-11-25 |
| FR2457303A1 (en) | 1980-12-19 |
| FR2457303B1 (en) | 1983-05-13 |
| CH643567A5 (en) | 1984-06-15 |
| SG37585G (en) | 1986-01-17 |
| CA1153761A (en) | 1983-09-13 |
| AU5856680A (en) | 1980-11-27 |
| IL60128A (en) | 1984-01-31 |
| SE431549B (en) | 1984-02-13 |
| IL60128A0 (en) | 1980-07-31 |
| DK162530C (en) | 1992-03-30 |
| DK162530B (en) | 1991-11-11 |
| SE8003761L (en) | 1980-11-22 |
| IT8067791A0 (en) | 1980-05-20 |
| DE3019250C2 (en) | 1982-11-11 |
| NL189201B (en) | 1992-09-01 |
| NL189201C (en) | 1993-02-01 |
| DE3019250A1 (en) | 1980-12-04 |
| BE883381A (en) | 1980-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR910004338B1 (en) | Physically modified beclomethasone dipropionate suitable for use in airosols | |
| US4044126A (en) | Steroidal aerosol compositions and process for the preparation thereof | |
| NO140303B (en) | PROCEDURE FOR TRANSFORMING AN ANTI-INFLAMMATORY EFFECTIVE STEROID SHOWING CRYSTAL GROWTH IN AEROSOL FUELS TO A FORM THAT DOES NOT SHOW SUCH CRYSTAL GROWTH | |
| EP2024383A2 (en) | Crystalline forms of 11 beta-(4-acetylphenyl)-20,20,21,21,21-pentafluor-17alpha- hydroxy-19-nor-17 -pregna-4,9-dien-3-one | |
| DE3005736C2 (en) | ||
| WO2001090137A2 (en) | NOVEL SOLID BODY FORMS OF MESOPROGESTIN 11β-[4E-(HYDROXYIMINOMETHYL)-PHENYL]-17α-METHOXYMETHYL-17β-METHOXY-ESTRA-4,9-DIEN-3-ONE | |
| US4273710A (en) | Process for preparing flunisolide | |
| GB2052506A (en) | Process for preparing a crystalline form of flunisolide | |
| DE3873200T2 (en) | NEW ANDROST-4-EN-3,17-DION DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. | |
| EP0401262B1 (en) | 24r-scymnol, and preparation and use thereof | |
| Kuhnert-Brandstätter et al. | Solvates and polymorphic modifications of steroid hormones. II | |
| DE1033199B (en) | Process for the preparation of dehydrosteroids | |
| GB2052507A (en) | Highly pure ursodeoxycholic acid and a process for producing it | |
| Kuhnert-Brandstätter et al. | Solvates and polymorphic modifications of steroid hormones. III | |
| US3098082A (en) | Process of extracting 3-amino compounds from the genus funtumia | |
| Thompson et al. | Preparation of Crystalline Anhydrous β-Gentiobiose | |
| DE2138426A1 (en) | New steroids and methods of making them | |
| US2876238A (en) | Purification process for 9alpha-fluorohydrocortisone compounds | |
| DE1618070C3 (en) | Process for the preparation of Gona-1,3,5 (10), 7-tetraenes and certain new Gona-1,3,5 (10), 7-tetraenes | |
| Inouye et al. | N-acylation of 2-amino-2-deoxy-D-glucose with mixed carboxylic acid anhydrides | |
| AT211965B (en) | Process for the preparation of compounds of the steroid series which are unsaturated in the 1- and / or 4- position | |
| DE1468988B1 (en) | 17alpha-chloroethynyl-13beta-ethyl-4- or -5 (10) -gon-3-ketones | |
| DE1087598B (en) | Process for the preparation of 21-amino-corticosteroids | |
| US3004995A (en) | Steroid compounds | |
| Nussbaum et al. | Reaction of Steroids with Diazomethane1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 711A | Proceeding under section 117(1) patents act 1977 | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000519 |