NL8002902A - PROCESS FOR PREPARING A CRYSTALLINE MODIFICATION OF FLUNISOLIDE AND CRYSTALLINE FLUNISOLIDE - Google Patents

Description

, * β-tr- N.O. 29 032

Process for the preparation of a crystalline modification of flunisolide, as well as crystalline flunisolide.

The invention relates to a method for obtaining a uniform crystalline form of flunisolide (hereinafter referred to as form A), as well as to crystalline flunisolide

Flunisolide is the common name in the United States of America of 6a-fluoro-116.21-dihydroxy-16a.l7oc-isopropylidene-dioxypregna-1,4-dien-3.20-dione. The group of compounds to which flunisolide belongs and methods for the preparation thereof are described in U.S. Pat. No. 3,126,375. These compounds develop anti-inflammatory and anti-pyretic activity and are mainly used to treat topical inflammation. Flunisolide can also be formulated with pharmaceutically suitable aerosol-based propellants and used to treat respiratory complaints such as atatma, allergic rhinitis, etc., in warm-blooded animals (see, for example, Belgian Patent 842,192). A particular polymorphic form (form A, a hemihydrate) of flunisolide has been found to be particularly stable in the form of preparations in the presence of aerosol-based propellants and is therefore preferred (see Belgian Patent Specification 842,192 cited). Due to the property of flunisolid in various polymorphic forms and also to develop crystalline properties in some of the solvents from which the product is crystallized, a process must be used which reproducibly produces the desired form A of flunisolide.

In US Pat. No. 3 * 126,375, as solvents for the crystallization of the group of steroids to which flunisolide belongs is ethyl acetate and methanol. However, when these solvents are used for the recrystallization of flunisolide, it appears that flunisolide with these solvents generally forms a clatrate, a solvate or a correspondingly included complex with the respective solvent. Such crystalline forms of flunisolide are undesirable due to the uniformity required for a pharmaceutically suitable aerosol formulation.

Belgian patent 842,192 discloses a process for the preparation of the form A of flunisolide. However, this process uses halogenated hydrocarbons, which have some undesirable properties.

It has been found that form A of flunisolide (a hemihydrate) can be obtained in a reproducible manner by the method of the invention. The process is characterized in that flunisolide 5 is crystallized from an aqueous solution of an alkanol of 3 or 4 carbon atoms. The crystals reproducibly obtained according to the invention form the form A, crystalline flunisolide. The result according to the invention is surprising, in particular on the basis that the form A is not obtained when flunisolide is recrystallized from an aqueous solution of methanol or ethanol.

The unique crystalline form of flunisolide obtained by the method of the invention is a hemihydrate, crystalline flunisolide, 6a-fluoro-11β.21-dihydroxy-16a.l7a-isopropylidenedioxy-15 pregna-1,4-dien-3.20-dione and is present case form A.

called i. The crystalline structure of the flunisolide of the invention in the form of a powder has an X-ray diffraction listed in Table A.

(table A) 8002902 -3- «Λ

Table A.

d Ι / Ijl ®

O

A% degrees 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 IQ 9.3 4.55 70 8-8 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 b = broad line, caused by the failure of solving 2 closely spaced lines.

son 2 9 02 -4-

A general discussion of the theory and definitions as well as the general method of X-ray diffractometry is set forth in Monograph National Formulary, XIII, pp. 902-904.

The reported X-ray diffraction values have been obtained according to the method described in Belgian Patent 842,192.

The form A of flunisolide is further characterized by the presence of 2.0 + 0.2% by weight of water. Since the calculated stoichiometric value in wt.% Of the water for a hemihydrate of flunisolide is 2.03 wt.%, The form A is assumed to be a hemihydrate.

The analysis of the water content of Form A can be carried out by any known analytical method. Generally, the analysis is performed using Karl Eischer reagent. The Karl Fischer analysis to determine water can be performed according to the original method reported in Angewandte Chemie 48, 594 (1955). However, the analysis is preferably performed using the automatic analyzer from Photovolt Corporation, Aquatest IT. The Aquatest IT analyzer is a coulometric titration device that includes a microprocessor control based on the specific and quantitative reaction of water with Karl.Fischer reagent. The special feature of the analyzer is that the reagent is supplied electronically, so that no standardization or calibration is required. The accuracy of the analyzer is + 10 µg or within 1%. In the determination of water in the form A of the flunisolide, where samples of 55 to 75 mg are taken, which contain between 700 and 1500 µg water, for the determination, the accuracy + 0.03% based on the amount of water is determined in yug.

The microprocessor control should distinguish the titration of the water present in the sample and a reaction of the Karl Fischer reagent with other reactants such as aldehydes or ketones. The Aquatest IT analyzer is operated as described in the instructions for use published by Photo-35 volt Corporation in July 1978 and in Paper no. 260, a publication of K.A.Lindblom (Pittsburg Conference on Analytical Chemistry and Applied Spectroscopy, February 1978). Photovolt Corporation's address is: 1115 Broadway, New York, New York 10010.

For the process according to the invention it is important that the device used for the crystallization of the flunisolide is 8002902

7 S

-5- uses is perfectly clean. If another polymorphic form of flun solid is present in the vessel or container in which the crystallization is carried out, the desired form A can be contaminated by another phase which is simultaneously formed and which is caused by the crystallization which is conducted by the present flunisolid crystals. Before the process according to the invention is carried out, the entire device must therefore be carefully washed with the alkanol to be used, for example water-containing n-butanol, to ensure that every amount of extra flunisolide of another crystal form has been completely removed from the device.

As mentioned, the process of the invention is characterized in that flunisolide is crystallized from an aqueous solution of an alkanol of 3 or 4 carbon atoms. For example, alkanols of 3 or 4 carbon atoms are isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, tert-butanol. N-butanol is preferred. The alkanol is water-containing, i.e. the alkanol contains about 0.2 to 5% by volume, preferably 1-4% by volume.

When n-butanol is used, about 2.3% by volume is used.

The flunisolide solution can be obtained in various ways. Any polymorphic form of flunisolide can be added to the alkanol or the alkanol can be added to the crystalline form and stirred until the flunisolide is completely dissolved.

The desired amount of water can then be added. However, aqueous alkanol can also be used for the preparation of the solution. To accelerate the dissolution process, the alkanol can be brought to a boiling point (e.g., 117 ° C for n-butanol) at a temperature of 75 ° C or higher.

In another embodiment, the alkanol can be added to a test solution of flunisolide in another solvent that has a lower boiling point than the alkanol. For example, n-butanol can be added to a solution of flunisolide in dichloromethane and the dichloromethane distilled off so that the n-butanol becomes the flunisolide solvent. This is performed by replacement distillation. Obviously, it is important to use a sufficient amount of alkanol to keep the flunisolide in solution. Water is then added. For example, the flunisolid concentration varies depending on the alkanol used. It has been found that about 50 g of flunisolide dissolve at 250 ° C in 250 ml of n-butanol containing 2% by volume of water and crystallize from the solution at about 35 ° C. the new crystalline form A being obtained.

After a solution of the flunisolide in the alkanol is obtained, the crystallization of the flunisolide is preferably carried out at a temperature below about 75 ° C. For example, this can be done by allowing the n-butanol solution to cool slowly, for example at a cooling rate of 1 ° per 30 seconds to about 10 minutes. The initial temperature of the aqueous alkanol solution can be from about 30 ° to about the boiling point of the alkanol.

Although the desired form A of the flunisolide can be obtained by crystallization by cooling only, such a method is not always economically efficient, since a relatively large amount of flunisolide remains dissolved. On a small scale, a suitable alkane solvent (in which the flunisolide has a low solubility) can be added to the alkanol solution to allow the flunisolide to exit the solution. The alkane solvent is preferably n-hexane or n-heptane. Generally, the volume of n-hexane or n-heptane used is from about 2 times to about 5 times the volume of the alkanol solution and becomes slow over an appropriate time, for example about 10 minutes to 4 hours or more depending on the volumes used solvents, added to the alkanol solution containing about 50 g of flunisolide. For example, 750 ml of n-hexane can be added to about 350 ml of an aqueous flunisolide solution in n-butanol in 1 hour. The alkane used as a solvent may have the same temperature as the n-butanol solution or may have a lower temperature, preferably room temperature, ie, about 20-25 ° C to accelerate crystallization.

The steroid crystals obtained are then dried in a manner known per se, such as by drying under reduced pressure to remove solvents. The drying time can be from 2 hours to several days. The unique crystalline structure of flunisolide with the X-ray diffraction values according to Table A and the structure of other polymorphic forms of flunisolide can be separated from each other by, for example, analysis of a powder by X-ray diffraction, the DSC method (differential scanning calorimetry), microscopy with polarized light, water analysis and microscopy in the heated state are distinguished.

8002902 \ * - * -7-

The following examples illustrate process conditions of the process of the invention.

Example I.

50 g of moisture-containing flunisolide (about 1 wt.% Water containing 5%) were placed in a 1 l Erlenmeyer flask equipped with a magnetic stirrer and 250 ml of n-butanol, which contained about 0.1 vol%, were added thereto. water. The mixture was heated to 50 ° C until the flunisolide was completely dissolved and then the solution was cooled slowly at a cooling rate of 1 ° per 10 minutes. Crystallization started at about 35 ° C and at 30 ° C, n-heptane was slowly added over a period of about 1 hour until the total volume of the mixture was 1 L. After the mixture was stirred at room temperature for 1 hour, the product was filtered, washed several times with n-heptane and air dried. The product was then dried in a vacuum oven at 50 ° C for three days, after which 45 g of flunisolide with the X-ray diffraction values listed in Table A were obtained.

Analysis of the crystals using Karl Fischer reagent in the Aquatest IV analyzer gave a water content of 1.95% by weight.

Example II.

100 g of flunisolide were placed in a 500 ml Erlenmeyer flask equipped with a magnetic stirrer and 196 ml of analytically pure n-butanol and 4 ml of distilled water were added thereto. The mixture was heated at 95 ° C with stirring until datol isolisolide was completely dissolved and the solution was cooled with stirring. Crystallization started at about 70 ° C. The resulting suspension was cooled to room temperature and stirred until the following day. The resulting product was filtered off and air dried. The yield was 85 g of flunisolide with the X-ray diffraction values listed in Table A.

The analysis of the crystals obtained using Karl Fischer reagent in the Aquatest gave a water content of 1.93% by weight.

Example III.

10 g of flunisolide were placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer and 15 ml of n-propanol and 0.6 ml of distilled water were added thereto. The mixture was heated to 90 ° G with stirring until the flunisolide 40 was completely dissolved and the solution was cooled with stirring.

8002902 -8-

Crystallization started at about 60 ° C and the resulting suspension was cooled to room temperature with stirring. After the mixture was stirred at room temperature until the next day, the resulting product was filtered off and air dried. 8.6 g of flunisolide having the X-ray diffraction values shown in Table I were obtained.

The analysis of the crystals using Karl Fischer reagent in the Aquatest IV yielded a water content of 2.08% by weight.

10 Example IY.

10 g of flunisolide were placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer and 20 ml of isopropanol and 1 ml of distilled water were added thereto. The mixture was heated to about 70 ° C until a clear solution was 15. and the solution was cooled with stirring. Crystallization started at 50-60 ° C. The resulting suspension was cooled to room temperature and stirred until the following day. After the mixture was kept at room temperature for 6 days, the resulting product was filtered off and air dried. The product was then dried at room temperature under reduced pressure for 24 hours. 8 5 S flunisolide with the X-ray diffraction values listed in Table A was obtained.

The analysis of the crystals using Karl Fischer reagent in the Aquatest IY gave a water content of 2.18% by weight. Example Y.

2 g of flunisolide with the X-ray diffraction values listed in Table A were placed in a vessel containing 10 ml of 95% methanol at room temperature. The mixture was heated with stirring until the total amount of the material had dissolved. The resulting solution was allowed to cool to room temperature while scratching the wall of the vessel with a glass rod to induce crystallization. The crystals obtained were analyzed microscopically using polarized light and found to be different from the initially used flunisolide.

35 Yoorbeeld YI.

The procedure of Example Y was repeated, however, the crystallization was induced by seeding with a small amount of fluorescent with the X-ray diffraction values listed in Table A. The resulting crystals were analyzed microscopically using polarized light and found to be other than 800 2 9 02 * * * -9- the flun isolide used as seed crystal material.

Image 711.

50 g of flunisolide were added to 600 ml of methanol and the mixture was heated to dissolve the flunisolide. Yervol-5 gens, the solution was cooled. The volume of the resulting solution was reduced by half by means of a rotary evaporator, then the resulting suspension was filtered and the crystalline flunisolide was isolated. The filtrate was again evaporated to a volume of about 60 ml and then filtered as mentioned. The resulting material was air dried. 26 g of flunisolide differing from the flunisolide with the X-ray diffraction values listed in Table A were obtained (analyzed by X-ray diffractometry. Dsc method, visual thermal analysis and determination of weight loss by temperature increase: 2, 6 wt%).

Figure 7 III.

100 mg of flunisolide were dissolved in 20 ml of absolute ethanol at about 70 ° C. The resulting solution was cooled to room temperature and the cooled solution was allowed to evaporate for a period of 3 days. The crystalline flunisolide obtained was analyzed by X-ray diffractometry, by the dsc method, by visual thermal analysis and by determination of the weight loss by temperature increase (4> 5; 4> 9 wt%). The crystalline flunisolide obtained was found to be different from the crystalline flunisolide having the X-ray diffraction values listed in Table A.

Example IX.

10 g of flunisolide were placed in a 50 ml Erlenmeymr flask equipped with a magnetic stirrer and 30 ml of tert-butanol and 1 ml of distilled water were added thereto.

The mixture was heated until a clear solution was obtained, then the solution was cooled with stirring until crystallization started. The resulting suspension was cooled to room temperature and stirred until the following day. The resulting mixture was filtered, the resulting product was air-dried and then dried at room temperature under reduced pressure for 24 hours. The resulting flunisolide had the X-ray diffraction values listed in Table A.

Analysis of the crystals using Karl Fiseher reagent in the Aquatest IY gave a water content of about 240 wt%.

8002902

Claims (7)

1. Process for the preparation of a crystalline form of flunisolide with a water content of 2.0 + 0.2% by weight with the X-ray diffraction values listed in Table A, characterized in that the steroid in question is crystallized from a solution of the stated steroid in a liquid alkanol with 3 or 4 carbon atoms containing 0.2-5% by volume of water. 2. Process according to claim 1, characterized in that a solution containing 1-4% by volume of water is used. Process according to claim 1 or 2, characterized in that the alkanol used is n-butanol. Process according to claim 1 or 2, characterized in that the alkanol used is isopropanol or n-propanol. 5. Process according to claim 1 or 2, characterized in that the solution is allowed to cool from a temperature above 75 ° C to a temperature below 75 ° C at which crystallization begins. 6. Process according to claims 1-5, characterized in that the solution is cooled to a temperature below 30 ° C. A crystalline form of flunisolide containing 2.0 + 0.2 wt.% Water with the X-ray diffraction values listed in Table A, obtainable according to any of claims 1 to 6. 8002902