JPS6258360B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a unique crystalline form of flunisolide (hereinafter referred to as Form A). Flunisolide is the name adopted in the United States for 6α-fluoro-11β,21-dihydroxy-16α,17α-isopropylidenedioxypregna-1,4-diene-3,20-dione. The type of compound to which flunisolide belongs and the method for producing it are described in US Pat.
Described in No. 3126375. These compounds exhibit flame and thermostable activity and have primary use in the treatment of local inflammation. Flunisolide has also been formulated with a pharmaceutically acceptable aerosol propellant and used to treat respiratory conditions such as asthma, allergic rhinitis, etc. in mammals (e.g. (see Belgian Patent No. 842192). One particular variant of flunisolide (Form A, hemihydrate) has been found to be particularly stable in the presence of an aerosol propellant composition and therefore suitable (see Belgian Patent No. 842,192, cited above). reference). However, due to the ability to create various polymorphic forms of flunisolide and the nature of the crystals, including some of the solvents in which the product is crystallized, the desired crystalline form A of flunisolide can be reproducibly produced. You must use a method that can generate US Pat. No. 3,126,375 to Ringgold et al.
Solvents used for crystallization of steroids, to which flunisolide belongs, include ethyl acetate and methanol. However, when these solvents are used to recrystallize flunisolide, flunisolide generally forms clathrates, solvates, or related complexes containing these solvents. This crystalline form of flunisolide is unacceptable because of the uniformity required for pharmaceutically acceptable aerosol compositions. Belgian patent no. 842192 describes a process for the preparation of flunisolide form A. However, this particular method uses halogenated hydrocarbons which have some undesirable properties. It has now been found that Form A (hemihydrate) of flunisolide can be obtained with good reproducibility by the method of the present invention. The method of the present invention has 3 to 3 carbon atoms.
It consists of crystallizing flunisolide from an aqueous solution of four alkanols. The crystals thus produced exhibit crystalline flunisolide of form A with good reproducibility. This is surprising, especially in view of the fact that Form A is not obtained when recrystallized from aqueous solutions of methanol or ethanol. The unique crystalline form of flunisolide produced by the process of the present invention is the hemihydrate crystalline form of flunisolide, namely 6α-fluoro-11β,21-dihydroxy-16α,17α-isopropylidenedioxypregnar 1,4-diene-3 , 20-dione, hereinafter referred to as Form A. This crystal structure has the powder X-ray diffraction pattern shown in Table A below.

【table】

[Table] The theory and definition of X-ray diffraction and general methods can be found in the National Formulary.
Formulary) Vol. 902-904. The above X-ray diffraction pattern is Belgian patent No. 842192.
Obtained by the method described in No. Flunisolide Form A is further characterized by the presence of 2.0±0.2% by weight of water. Since the calculated water to hemihydrate stoichiometry of flunisolide is 2.03%, Form A appears to be a hemihydrate. Analysis of the water content of Form A may be performed by any suitable analytical method. Generally, the analysis is performed using Karl Fischer reagents. The Karl-Fitscher analysis method for water was published in Angewandte Chemie, No. 48.
This can be carried out by the method described in Vol. 394, 1935. Preferably, however, the analysis is carried out by Photovolt Corporation.
The test is carried out using an automatic analyzer, model Aquatest, manufactured by J.D. Corporation. Aquatest is a coulometric analyzer with integrated microprocessor control and is based on the specific and quantitative reaction of water with Karl-Fitscher reagent. This device is unique in that the reagents are generated electrolytically and there is no need for standardization or calibration. The accuracy of the device is ±10 μg or 1%, whichever is greater. When determining the water content in flunisolide type A, the sample size for determination is selected between 35 mg and 75 mg, and 700 μg
It contains ~1500 μg of water, with an accuracy of ±0.03% of the amount of water determined in μg. The microprocessor control helps distinguish between titrations with water present in the sample and reactions of the Karl-Fitscher reagent with other components, such as aldehydes or ketones. Aqua test is
As set forth in the Guidance Manual published by Fotovoort Corporation in July 1978, and by K.A. Lindblom (KA.
Lindblom) February 1978 Pittsburgh Conference Report on Analytical Chemistry and Applied Spectroscopy
Operated by method No.260. Huotovault Corporation's address is 1115 Broadway.
New York, New York 10010. In the method of the invention, it is important that the equipment used for crystallizing flunisolide is completely clean. If other polymorphs of flunisolide are present in the flask or container in which crystallization occurs, the desired Form A will be contaminated with other phases that are simultaneously formed by crystallization directed by the existing crystalline form of flunisolide. sell. That is, before carrying out the process of the invention, all equipment should be thoroughly washed with an aqueous solution of the alkanol used, for example n-butanol, so that excess flunisolide of different crystalline forms is completely removed from the equipment. is preferred. As mentioned above, the method of the present invention is a method for crystallizing flunisolide from an aqueous solution of an alkanol having 3 or 4 carbon atoms. Examples of alkanols having 3 or 4 carbon atoms include isopropyl alcohol, n-propanol, n-butanol,
Includes isobutyl alcohol, sec-butyl alcohol, and t-butyl alcohol. n-Butanol is preferred. Alkanols are aqueous solutions. That is, it contains about 0.2 to 5% by volume of water, preferably 1 to 4% by volume. If n-butanol is used, about 2.3% by volume is used. Flunisolide solution can be obtained in several ways. Any polymorph of flunisolide can be added to the alkanol or the alkanol can be added to the flunisolide and stirred until the flunisolide is completely dissolved. The desired amount of water can then be added. However, when preparing the solutions it is also possible to use aqueous alkanols. To accelerate the dissolution process, the alkanol should be added at 75%
It can be heated to a temperature of 0.degree. C. or higher up to the boiling point (eg 117.degree. C. for n-butanol). Alternatively, the alkanol can be added to a solution containing 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 can be distilled off while the n-butanol becomes a solvent for flunisolide. This can be done by displacement distillation. It is of course important to use sufficient alkanol to keep the flunisolide in solution. Then add water. The concentration of flunisolide therefore varies depending on the alkanol used. Approximately 50g of flunisolide
New crystalline form A is obtained by dissolving in 250 ml of n-butanol containing 2% V/V water at 80 DEG C. and crystallizing from the solution at about 35 DEG C. Once the alkanolic solution of flunisolide is obtained, crystallization of flunisolide preferably occurs at approximately 75%
It is carried out at temperatures below °C. For example, this is n
- This can be carried out by gradually cooling the butanol solution at a rate of 1° C., for example every 30 seconds to about 10 minutes. The desired flunisolide form A can be obtained by crystallization by cooling alone, but such a method is not always economically advantageous since a large amount of flunisolide remains in solution. On a small scale, a suitable alkane solvent (in which flunisolide has a low solubility) can be added to the alkanol solution and flunisolide can be crystallized from the solution. Preferably, the alkane solvent is n-hexane or n-heptane. Generally, the volume of n-hexane or n-heptane added is from about 2 to about 5 times the volume of the alkanol solution and, depending on the volume of solvent used, for an extended period of time, such as from about 10 minutes to 4 hours or more. Gradually add to the alkanol solution containing about 50 g of flunisolide. For example, 750ml n
- hexane over 1 hour aqueous n-butanol/
Add to approximately 250 ml of flunisolide solution. The alkane solvent can be at the same temperature as the n-butanol solution or lower, but ambient temperature, ie, about 20-25°C, is preferred to promote crystallization. Once the steroid crystals are obtained, they are dried to remove the solvent by methods known in the art, such as vacuum drying. This can be done for 2 hours to several days. The unique crystal structure of flunisolide, which has the X-ray diffraction pattern of Table A above, can be analyzed by, for example, X-ray powder diffraction analysis, differential scanning calorimetry analysis, polarization microscopy, water analysis and hot stage microscopy.
can be used to distinguish it from other polymorphs of flunisolide. Although the following examples illustrate certain representative conditions of the method of the invention, they should not be construed as limiting the scope of the claims. Example 1 50 g of wet (containing about 1% water by weight) flunisolide are placed in one Erlenmeyer flask equipped with a magnetic stirrer and containing about 0.1% water by volume.
Add 250 ml n-butanol. The mixture is heated to 70°C until completely dissolved, and then the solution is gradually cooled at a rate of about 1°C/min. Crystallization is found to occur at about 35°C and n-heptane is added gradually over about 1 hour until the total volume of the mixture reaches 1 at 30°C. After stirring for an additional hour at room temperature, the product is filtered, washed several times with n-heptane, and air dried. 50 of this substance
Flunisolide dried in a vacuum oven for 3 days at °C and having a powder X-ray diffraction pattern as shown in Table A above.
Obtained 45g. Photovolt's Aquatest
Analysis of the crystals using Karl-Fitscher reagent (Aquatest) revealed that the water content was 1.93%.
It was hot. Example 2 100g of flunisolide was added to a 500g tube equipped with a magnetic stirrer.
ml Erlenmeyer flask, 196ml
of analytical grade n-butanol and 4 ml of distilled water are added. Heat and stir the mixture to 95° C. until complete dissolution, then cool the solution while stirring.
It can be seen that crystallization occurs at about 70°C. The resulting slurry is cooled to room temperature and stirred overnight. The product is then filtered and air dried. 85 g of flunisolide having the powder X-ray diffraction pattern shown in Table A above was obtained. Analysis of the crystals obtained using the Karl-Fitscher reagent in Fotovoort's Aquatest revealed that the water content was 1.93%. Example 3 10g of flunisolide in 50ml with magnetic stirrer
into an Erlenmeyer flask and add 15 ml of n
- Add propanol and 0.6 ml distilled water. Heat and stir the mixture to 90° C. until complete dissolution, then cool the solution while stirring. about 60
Crystallization was found to occur at 0.degree. C. and the resulting slurry was cooled to room temperature with stirring. After stirring overnight at room temperature, the product was filtered and air dried to yield 8.6 g of flunisolide having the powder X-ray diffraction pattern shown in Table A above. Analysis of the crystals using a Karl-Fisscher reagent on a photovoltaic AquaSet revealed that the water content was 2.08% by weight. Example 4 10g of flunisolide in 50ml with magnetic stirrer
into an Erlenmeyer flask and add 20 ml of isopropyl alcohol and 1 ml of distilled water. The mixture is heated to about 70° C. until completely dissolved and then cooled with stirring. Crystallization becomes evident at 50-60°C. The resulting slurry is cooled to room temperature and stirred overnight. After standing at room temperature for 6 days, the product was filtered, air dried, and vacuum dried at room temperature for 24 hours to obtain 8.5 g of flunisolide having the powder X-ray diffraction pattern shown in Table A above. Analysis of the crystals using the Karl-Fitscher reagent in Photovolt's Aquatest revealed that the water content was 2.18%. Example 5 2 g of flunisolide having the X-ray diffraction pattern shown in Table A above was added to 95% ethanol at room temperature.
Add to flask containing 10 ml. The mixture was heated with stirring until all materials were completely dissolved. The resulting solution is then cooled to room temperature while the side walls of the flask are scratched with a glass rod to induce crystallization. The obtained crystals were analyzed using polarized light microscopy and found to be different from the flunisolide originally used. Example 6 The method of Example 5 was repeated, but X in Table A
A small amount of flunisolide, which has a line diffraction pattern, was added as a seed to induce crystallization. The thus obtained crystals were analyzed using polarized light microscopy and found to be different from the flunisolide used as a seed product. Example 7 Add 50g of flunisolide to 600ml of methanol,
Heat to dissolve all flunisolide,
Then, it was allowed to cool. The volume of the resulting solution was reduced by half in a rotary evaporator and the resulting slurry was then filtered to isolate crystalline flunisolide. The liquid was re-evaporated to a volume of approximately 60 ml and filtered again as before. The resulting material was air dried and weighed 26 g.
of flunisolide was obtained. This item is shown in Table A
It was different from those with a line diffraction pattern (analysis by X-ray diffraction, differential scanning calorimeter analysis, visual thermal analysis, weight loss on heating 2.6%). Example 8 100 g of flunisolide was dissolved in 20 ml of absolute ethanol at about 70°C. The resulting solution is cooled to room temperature and evaporated over 3 days. The obtained crystalline flunisolide was collected and subjected to X-ray diffraction, differential scanning calorimeter analysis, visible thermal analysis, and weight loss by heating (4.5
%, 4.9%). The crystalline flunisolide obtained was found to be different from the crystalline flunisolide exhibiting the X-ray diffraction pattern in Table A. Example 9 10 g of flunisolide in 50 ml with magnetic stirrer
into a 20 ml Erlenmeyer flask.
- Add butyl alcohol and 1 ml of distilled water. The mixture is heated until a clear solution is obtained and then cooled with stirring until crystals appear. The resulting slurry is cooled to room temperature and stirred overnight. The resulting mixture was filtered and air-dried for 24
After drying under vacuum at room temperature for an hour, flunisolide having a powder X-ray diffraction pattern shown in Table A was obtained. The water content was approximately 2% by weight when the crystals were analyzed with Karl-Fitscher reagent using a PhotoVault Aquatest.

Claims (1)

[Scope of Claims] 1 3 to 4 carbon atoms containing 0.2 to 5% by volume of water
X-ray diffraction, characterized by the crystallization of flunisolide from a solution of flunisolide in a liquid alkanol containing 2.0 ± 0.2% by weight of water and as described in Table A below. A method for producing flunisolide in a crystalline form exhibiting a pattern. 2. The method of claim 1, wherein the solution contains 1 to 4% by volume of water. 3. The method according to claim 1 or 2, wherein the alkanol is n-butanol. 4. The method according to claim 1 or 2, wherein the alkanol is isopropyl alcohol or n-propyl alcohol. 5 Heat the alkanol solution to 75°C from a temperature higher than 75°C.
The method according to claim 1 or 2, wherein the method is cooled to a lower temperature and crystallization occurs at that temperature. 6. The method according to claims 1 to 5, wherein the solution is cooled to a temperature lower than 30°C.