CA1153761A - Process for preparing flunisolide - Google Patents
Process for preparing flunisolideInfo
- Publication number
- CA1153761A CA1153761A CA000352333A CA352333A CA1153761A CA 1153761 A CA1153761 A CA 1153761A CA 000352333 A CA000352333 A CA 000352333A CA 352333 A CA352333 A CA 352333A CA 1153761 A CA1153761 A CA 1153761A
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- CA
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- Prior art keywords
- flunisolide
- solution
- alkanol
- water
- butanol
- Prior art date
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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]
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- 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
Abstract of the Invention A unique crystalline form of flunisolide is prepared by crystallizing flunisolide from a solution of 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
7~
PROCESS FOR PREPARING A CRYSTALLINE MODIFICATION
OF FLUNISOLIDE
_.
Field of the Invention This invention relates to a process for making a unique crystalline form of flunisolide (hereafter Form ~).
Prior Art Flunisolide is the United States adopted name Eor 6a fluoro~ ,21-dihydroxy-16a,17a-isopropylidenedioxy-pregna-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 anti~in1ammatory and anti-pyretic activity and have primary utility in the treatment of topical inflammation. Flunisolide 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. ~42rl92). One particular polymorphic form (Form A, a hemihydrate) of 1unisolide has been found to be particularly stable in the presence of aerosol prope~lant formulations and therefore is preferred (see the aforementioned Belgian Patent No~
B~2,192). However, because of thé ability of flunisolide to form various polymorphic foxms as well as to form crystal habits which include some of the solvents from JJ7~
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. ~owever, that particular process employs halogenated hydrocarbons which have some undesirable properties.
Summary and Preferred Embodiments 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 fluni-solide. 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 hemi-hydrate, crystalline flunisolide, 6a-fluoro~ ,21-dihydroxy-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione and is referred to herein as Form A The crystalline structure has a powder X-ray diffraction 19270~EPO
76~
pattern as indicated in Table A, belowO
Table A
. I/Il O
A % deg.
10.04 50 4-4 9.82 60 ~.5 9.30 80 4.8 7.69 50 5~8 6.91 ~0 6.4 6.32 10 7.0 5.98 90 7.4 5.53 100 i3.0 5.21 60 8.5 5.06 60 8.8 15 . 4.79 10 9.3 4.55 70 9.8 4.33 1 10.3 4.13 10 10.8 3.~5 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
PROCESS FOR PREPARING A CRYSTALLINE MODIFICATION
OF FLUNISOLIDE
_.
Field of the Invention This invention relates to a process for making a unique crystalline form of flunisolide (hereafter Form ~).
Prior Art Flunisolide is the United States adopted name Eor 6a fluoro~ ,21-dihydroxy-16a,17a-isopropylidenedioxy-pregna-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 anti~in1ammatory and anti-pyretic activity and have primary utility in the treatment of topical inflammation. Flunisolide 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. ~42rl92). One particular polymorphic form (Form A, a hemihydrate) of 1unisolide has been found to be particularly stable in the presence of aerosol prope~lant formulations and therefore is preferred (see the aforementioned Belgian Patent No~
B~2,192). However, because of thé ability of flunisolide to form various polymorphic foxms as well as to form crystal habits which include some of the solvents from JJ7~
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. ~owever, that particular process employs halogenated hydrocarbons which have some undesirable properties.
Summary and Preferred Embodiments 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 fluni-solide. 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 hemi-hydrate, crystalline flunisolide, 6a-fluoro~ ,21-dihydroxy-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione and is referred to herein as Form A The crystalline structure has a powder X-ray diffraction 19270~EPO
76~
pattern as indicated in Table A, belowO
Table A
. I/Il O
A % deg.
10.04 50 4-4 9.82 60 ~.5 9.30 80 4.8 7.69 50 5~8 6.91 ~0 6.4 6.32 10 7.0 5.98 90 7.4 5.53 100 i3.0 5.21 60 8.5 5.06 60 8.8 15 . 4.79 10 9.3 4.55 70 9.8 4.33 1 10.3 4.13 10 10.8 3.~5 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.~
2.60 1 17.3 ~.56 1 17.
2.~0 3 . 18.8 2.31 1 19.5 `~-. . 2.2~ . 1 19~8 .2.13 1 21.3 : 2.10 1 21.
1.97 1 23.0 1.~8 2 24.3 b = broad line due to failure to resolve two closeiy spaced lines.
~5~76:~
A general discussion of the theory and definitions as well as the general procedur~ of X-ray diffractometry is set forth in the monograph at pages 902-904 of the National Formulary, XIII.
S The above X ray diffraction pattern was obtained in accordance with the method described in Belyian 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 a hemihydrate 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 incorpo-rates microprocessor control and is based on the speciEic and quantitative reaction of water with Karl Fischer reagent. The instrwQent is unique in that the reagent is generated electronically which eliminates the need for standardization or calibration. The accuracy of the instrument i5 within + 10 micrograms (mcg) or 1% which ~ ever is greater. For determination of water in fluniso-lide Form A, where ~he sample sizes chosen for the deter-minations are between 35 mg and 75 mg and contain between 700 mcg and 1500 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 an~
35 any reaction of the Karl Fischer reagent with other entities such as aldehydes or ketones. The Aqua~ po 7f~
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 oE Photovolt Corporation is 1115 Broadway, New York, New York 10010.
In the process of this invention it is important that the equipmen~ ~hat is used for the crystallization of flunisolide is completely clean. If there is another polymorphic form of flunisolide present in the flask or con~ainer in which the crystallization takes place the desired form A may be contaminated with another phase which is formed simultaneously due to the crystallization which is directed by the existing crystals of fluniso-lide. Thus, before performing the process of the inven~
tion 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 i5 completely removed from the equipment.
As pointed out previously, the process of -the inven~
tion 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, n-propanol, n-butanol, isobutyl alco-hol, sec butyl alcohoi, tert-butyl alcohol. N-butanol is preferred. The alkanol is aqueous, that is, it contains about ~.2 to 5~ water by volume, and preferably contains 1 to 4~ water by volume~ With n-butanol, about 2.3~ by volume is used.
The flunisolide 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. Tlerea~ter, the desired amount of water can be added. However, for the preparation of the 76~
~6-solution, aqueous alkanol also can be used. In order to speed the process of solution the alkanol can be heated to a temperature of 75C or more, up to it~ boiling poin~
(e.g. for n-butanol 117C). 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 solu-tion of flunisolide in methylene chloride and the methyl-e~e chloride distilled off while n-butanol becomes the solvent for flunisolide. This is done through replace-ment distillation~ It is important of course, to use sufficien~ 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 ~ound that about 50 grams of flunisolide will dissolve at 80C in 250 milliliters (ml) of n-butanol containing 2~
v/v water and crystallize from solution at about 35C and give the new crystalline form A.
Once a solution of flunisolide in the alkanol is obtained, the crystallization of the 1unisolide is effected, preferably at a temperature of less than about 75C. 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 alkanol solution can be anywhere from about 30C 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 ~5i^37~i~
.
preferably n-hexane or n-heptane. ~,enerally 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. o flunisolide over an extended period o~ 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 n-butanol solution, or less, but preferably is at ambient tempera-ture, iOe., about 20-25C 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 unique 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 micro-scopy, 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 limit-ing the scope of the claims appended hereto.
.
Fifty (50) grams (g) of damp flunisolide (containing about 1% by weight water) are placed in a 1 liter Erlenmeyer flask provided with maqnetic stirring, and 2$0 milliliters ~ml) of n-butanol containing about 0.1% by volume water is added. The mixture is heated to 70 until complete dissolution i5 achieved and then the solution is left to cool slowly at approximately 1 degree --8-- .
, per minute. At about 35C crystallization become~
apparent and at 30C 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 50C ~or three days to yield 45 grams of flunisolide having a powdee X-ray diffraction pattern set ~orth in Table A.
Analysis of the crystals using Karl Fischer reagent in Photovol " s Aquatest IV gives 1.93% water.
One hundred ~100~ grams of flunisolide are placed in a 500 ml Erlenmeyer flask provide~ with magnetic stir-ring, and 196 ml analytical grade n-butanol and 4 ml distilled water are added. The mixture i5 heated with stirring to 95C. until complete dissolution is achieved, then cooled with stirring. At about 70 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. flunisolid~ having the powder X-ray diffraction pattern set ~orkh in Table Au Analysis of the resulting crystals using Karl Fisçher reagent in Photovolt's Aquatest gives 1.93 w/water.
., `- EXAMPLE 3 Ten (10) grams of flunisolide are placed in a 50 ml ~rlenmeyer flask provided with magnetic stirring and 15 ml n-propanol plus 0.6 ml distilled water added. The mixture is heated with stirring to 90C. until complete dissolution is achieved, then cooled with stirring.
Crystallization becomes apparent at about 60, and the 6~
9, resulting slurry is cooled with stirrin~ to room tempera~
ture~ After overni~ht stirring at room temperatu~e, the product is filtered and air dried, giving 8.6 g fluniso-lide 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 2.08% w/water.
EX~MPLE 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 70C. until a clear solu-tion is obtained, then cooled with stirring. Crystalli-zation becomes evident at 50-60C. 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 IY gives ~.18~ water.
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 tempera-- ture. The mixture was heated with stirring until all of the material is entirely dissolved. The resulting solu-tion 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 dif~erent than the flunisolide used initially.
19 270-~po ~'J7 EX~MæLE 6 The procedure of Example 5 was repeated except that crystallization was induced by seeding with a small amount of flunisolide having the X-ray diffraction pattern of Table A. The resulting cyrstals so obtained - were analyzed using polarized light microscopy and were found to differ from the flunisolide used as seed crystals.
.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 50 ml. volume, then filtered again as above. The resultant material was air dried, giving 26 gms oE flunisolide which difers (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.
One hundred (100) mg flu~isolide was dissolved in 20 ml absolute ~thanol at approximately 70C. The - resulting solution was cooled to room temperature and allowed to evaporate over a three day period. The resultant crystalline ~lunisolide was collected, analyzed by X-ray diffractometry, differential scanning calori-metry, visual thermal analysis, and weight loss on heat-ing (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.
` ~5~7~
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 tempera-ture and stirred overnight. The resulting mixture is filtered, air dried and dried in vacuo at room tempera-ture for 24 hours to giYe flunisolide 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 about 2% by weight water.
.
2.60 1 17.3 ~.56 1 17.
2.~0 3 . 18.8 2.31 1 19.5 `~-. . 2.2~ . 1 19~8 .2.13 1 21.3 : 2.10 1 21.
1.97 1 23.0 1.~8 2 24.3 b = broad line due to failure to resolve two closeiy spaced lines.
~5~76:~
A general discussion of the theory and definitions as well as the general procedur~ of X-ray diffractometry is set forth in the monograph at pages 902-904 of the National Formulary, XIII.
S The above X ray diffraction pattern was obtained in accordance with the method described in Belyian 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 a hemihydrate 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 incorpo-rates microprocessor control and is based on the speciEic and quantitative reaction of water with Karl Fischer reagent. The instrwQent is unique in that the reagent is generated electronically which eliminates the need for standardization or calibration. The accuracy of the instrument i5 within + 10 micrograms (mcg) or 1% which ~ ever is greater. For determination of water in fluniso-lide Form A, where ~he sample sizes chosen for the deter-minations are between 35 mg and 75 mg and contain between 700 mcg and 1500 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 an~
35 any reaction of the Karl Fischer reagent with other entities such as aldehydes or ketones. The Aqua~ po 7f~
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 oE Photovolt Corporation is 1115 Broadway, New York, New York 10010.
In the process of this invention it is important that the equipmen~ ~hat is used for the crystallization of flunisolide is completely clean. If there is another polymorphic form of flunisolide present in the flask or con~ainer in which the crystallization takes place the desired form A may be contaminated with another phase which is formed simultaneously due to the crystallization which is directed by the existing crystals of fluniso-lide. Thus, before performing the process of the inven~
tion 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 i5 completely removed from the equipment.
As pointed out previously, the process of -the inven~
tion 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, n-propanol, n-butanol, isobutyl alco-hol, sec butyl alcohoi, tert-butyl alcohol. N-butanol is preferred. The alkanol is aqueous, that is, it contains about ~.2 to 5~ water by volume, and preferably contains 1 to 4~ water by volume~ With n-butanol, about 2.3~ by volume is used.
The flunisolide 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. Tlerea~ter, the desired amount of water can be added. However, for the preparation of the 76~
~6-solution, aqueous alkanol also can be used. In order to speed the process of solution the alkanol can be heated to a temperature of 75C or more, up to it~ boiling poin~
(e.g. for n-butanol 117C). 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 solu-tion of flunisolide in methylene chloride and the methyl-e~e chloride distilled off while n-butanol becomes the solvent for flunisolide. This is done through replace-ment distillation~ It is important of course, to use sufficien~ 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 ~ound that about 50 grams of flunisolide will dissolve at 80C in 250 milliliters (ml) of n-butanol containing 2~
v/v water and crystallize from solution at about 35C and give the new crystalline form A.
Once a solution of flunisolide in the alkanol is obtained, the crystallization of the 1unisolide is effected, preferably at a temperature of less than about 75C. 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 alkanol solution can be anywhere from about 30C 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 ~5i^37~i~
.
preferably n-hexane or n-heptane. ~,enerally 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. o flunisolide over an extended period o~ 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 n-butanol solution, or less, but preferably is at ambient tempera-ture, iOe., about 20-25C 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 unique 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 micro-scopy, 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 limit-ing the scope of the claims appended hereto.
.
Fifty (50) grams (g) of damp flunisolide (containing about 1% by weight water) are placed in a 1 liter Erlenmeyer flask provided with maqnetic stirring, and 2$0 milliliters ~ml) of n-butanol containing about 0.1% by volume water is added. The mixture is heated to 70 until complete dissolution i5 achieved and then the solution is left to cool slowly at approximately 1 degree --8-- .
, per minute. At about 35C crystallization become~
apparent and at 30C 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 50C ~or three days to yield 45 grams of flunisolide having a powdee X-ray diffraction pattern set ~orth in Table A.
Analysis of the crystals using Karl Fischer reagent in Photovol " s Aquatest IV gives 1.93% water.
One hundred ~100~ grams of flunisolide are placed in a 500 ml Erlenmeyer flask provide~ with magnetic stir-ring, and 196 ml analytical grade n-butanol and 4 ml distilled water are added. The mixture i5 heated with stirring to 95C. until complete dissolution is achieved, then cooled with stirring. At about 70 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. flunisolid~ having the powder X-ray diffraction pattern set ~orkh in Table Au Analysis of the resulting crystals using Karl Fisçher reagent in Photovolt's Aquatest gives 1.93 w/water.
., `- EXAMPLE 3 Ten (10) grams of flunisolide are placed in a 50 ml ~rlenmeyer flask provided with magnetic stirring and 15 ml n-propanol plus 0.6 ml distilled water added. The mixture is heated with stirring to 90C. until complete dissolution is achieved, then cooled with stirring.
Crystallization becomes apparent at about 60, and the 6~
9, resulting slurry is cooled with stirrin~ to room tempera~
ture~ After overni~ht stirring at room temperatu~e, the product is filtered and air dried, giving 8.6 g fluniso-lide 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 2.08% w/water.
EX~MPLE 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 70C. until a clear solu-tion is obtained, then cooled with stirring. Crystalli-zation becomes evident at 50-60C. 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 IY gives ~.18~ water.
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 tempera-- ture. The mixture was heated with stirring until all of the material is entirely dissolved. The resulting solu-tion 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 dif~erent than the flunisolide used initially.
19 270-~po ~'J7 EX~MæLE 6 The procedure of Example 5 was repeated except that crystallization was induced by seeding with a small amount of flunisolide having the X-ray diffraction pattern of Table A. The resulting cyrstals so obtained - were analyzed using polarized light microscopy and were found to differ from the flunisolide used as seed crystals.
.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 50 ml. volume, then filtered again as above. The resultant material was air dried, giving 26 gms oE flunisolide which difers (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.
One hundred (100) mg flu~isolide was dissolved in 20 ml absolute ~thanol at approximately 70C. The - resulting solution was cooled to room temperature and allowed to evaporate over a three day period. The resultant crystalline ~lunisolide was collected, analyzed by X-ray diffractometry, differential scanning calori-metry, visual thermal analysis, and weight loss on heat-ing (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.
` ~5~7~
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 tempera-ture and stirred overnight. The resulting mixture is filtered, air dried and dried in vacuo at room tempera-ture for 24 hours to giYe flunisolide 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 about 2% by weight water.
.
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a crystalline form of flunisolide which contains 2.0 ? 0.2% by weight water exhibits an X-ray diffraction pattern as set forth in Table A.
Table A
which 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.
Table A
which 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 wherein said solution is cooled to a temperature below 30 degrees C.
4. The process of claim 1, 2 or 3 wherein said alkanol is n-butanol.
5. The process of claim 1, 2 or 3 wherein said alkanol is isopropyl alcohol or n-propyl alcohol.
6. The process of claim 1, 2 or 3 wherein said alkanol solution is allowed to cool from a temperature above 75 degrees C to a temperature below 75 degrees C at which crystallization takes place.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4083079A | 1979-05-21 | 1979-05-21 | |
| US40,830 | 1979-05-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1153761A true CA1153761A (en) | 1983-09-13 |
Family
ID=21913206
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000352333A Expired CA1153761A (en) | 1979-05-21 | 1980-05-21 | Process for preparing 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 |
| AU5856680A (en) | 1980-11-27 |
| IL60128A (en) | 1984-01-31 |
| GB2052506A (en) | 1981-01-28 |
| 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 |
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