DE3019250C2 - Process for the preparation of a crystalline form of flunisolide - Google Patents

Description

d / Ä r / i, % egrad 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 5 " 11.5 3.70 5 12.0 3.63 10 12.3 3.'f> 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 \ 16.8 2.63 17.0 2.60 17.3 2.56 17.5 2.40 18.8 2.31 19.5 2.28 19.8 2.13 21.3 2.10 21.5 1.97 23.0 1.88 ; 24.3 3 \

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by crystallizing the steroid from a solvent, characterized in that the solvent used is an alkane! with 3 or 4 carbon atoms, which contains 0.2 to 5 VolL ⁰ Zo water, is used.

fertilize. Flunisolide can also be used with pharmaceutical grade compatible aerosol propellants and formulated for the treatment of respiratory diseases, such as asthma, allergic rhinitis, etc., in humans and animals can be used (see e.g. BE-PS 8 42 192). One special polymorphic form (form A, a hemihydrate) des Runisolid has proven to be particularly stable in the presence of aerosol propellant formulations and is therefore preferred (cf. the above-mentioned BE-PS 8 42 192). However, since flunisolide Has ability to form various polymorphic shapes and can also form crystals that are somewhat des Solvent from which the product is crystallized, a process must be applied which in a reproducible manner yields the form A of flunisolide.

In US-PS 31 26 375 include the crystallization of the steroid family to which FlunisoVd belongs, solvent used e.g. B. ethyl acetate and methanol. However, these solvents are used to Recrystallization of flunisolide was used, then it was found that the fiunisolide is generally a ciathrate, Solvate or a related solvent inclusion complex with these Solvent forms these crystal forms of the Huniso-Iid are unacceptable due to the uniformity required for a pharmaceutically portable aerosol formulation

In BE-PS 8 42 192 a process for the preparation of form A of flunisolide is described. However, this particular process uses halogenated hydrocarbons, which are certain undesirable Have properties.

It has now been found that Form A of flunisolide (a hemihydrate) can be reproduced can be produced by the process of the invention. The procedure is characterized by that flunisolide is crystallized from an aqueous solution of an alkanol having 3 or 4 carbon atoms. In the Crystals formed in this way show in a reproducible manner the form A, namely crystalline flunisolide. This is surprising, especially in view of the fact that when recrystallization of flunisolide Form A is not obtained from an aqueous solution of methanol or ethanol.

The unique crystalline produced according to the invention Form of flunisolide is a hemihydrate crystallized flunisolide, namely 6 Λ-fluoro-11 0.21 -dihydroxy- 16 ", 1 /- isopropylidendioxypregna-1,4-diene-3.20-dione, and is referred to below as Ft / m A. The crystalline structure has a powder X-ray breakdown pattern according to the following table A.

In the following table means

The present invention relates to a method for producing a unique, crystalline Form of flunisolide (hereinafter referred to as Form A, Table A). 60

In the USA, flunisolide is the common name for d, A 6A- ¹ FlUOr-I I ß, 2 \ -a \ hydro) iyA6A, \ 7 Ä-isöpropyljden '· dioxy-pregna-1 ₎ 4-diene ⁱ 3,2Ö- dione- The class of compounds to which flunisolide belongs and processes for their preparation are described in US Pat. because two lines that are close together could not be separated.

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A general discussion of theory and definitions as well as the general procedure of the X-ray diffractometry is found on pages 902 to 904 of the National Formulary, XIII.

The above X-ray diffraction pattern was found after the procedure of BE-PS 8 42 192 obtained.

Form A of flunisolide can be further characterized by the presence of 2.0 ± 02 % by weight of water. Since the calculated stoichiometric weight percentage of water for a hemihydrate of flunisolide is 2.03%, Form A appears to be a hemihydrate.

The analysis of form A for water content is carried out by any suitable analytical method, in general using a Karl Fischer reagent. The Karl Fischer analysis on water can after original procedure in Angew. Chemie 48, 394 (1935); however, it is preferably under Use of the automatic analysis device Aquatest IV from Photovolt Corp. carried out. The Aquatest IV device is a coulometric titrator that is microprocessor controlled introduces and on the specific and quantitative reaction of water with the Karl Fischer reagent based. The instrument is unique in that the reagent is formed electronically, which requires a Standardization or calibration eliminated. The accuracy of the instrument is within ± 10 micrograms (meg) or 1% (whichever who! each is larger). For water determination in form A. From flunisolide were those chosen for the determination ' The sample size was between 35 and 75 mg and contained between 70 and 1500 meg of water Accuracy within ± 0.03% of the amount of water, determined in meg.

The microprocessor control is used to distinguish between what is present in the sample Titration water and any reaction of the Karl Fischer reagent with other compounds such as aldehydes or ketones. The Aquatest IV is carried out according to the instruction manual of the Photovolt Corp. from July 1978 and according to publication no. 260, submitted to the Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, Feb. 1978 by K. A. Lindblom (Photovolt Corp, 1115 Broadway, New York, USA).

In the process according to the invention it is important that the apparatus used for the crystallization of flunisolide is completely clean. There is another polymorphic in the flask or container to carry out the crystallization If the form of the flunisolide is present, the desired form A can be contaminated with another phase t ^ in, simultaneously due to the by the Crystallization caused by the presence of crystals of flunisolide is formed. Before performing the It is therefore expedient to process according to the invention the device thoroughly with the alkanol to be used, e.g. B. aqueous n-ButanoI to wash ensure that any other flunisolide of a different crystal form is completely out of this away.

As mentioned above, the process according to the invention is characterized in that flunisolide alkanols with 3 or 4 carbon atoms crystallize from an aqueous solution of an alkanol with 3 or 4 carbon atoms include e.g. B. isopropyl alcohol, n-propanol, n-butanol, isobutyl alcohol, secondary butyl alcohol, tert-butyl alcohol, n-butanol is preferred. The alkanol is aqueous; H. it contains about 0.2 to 5% by volume of water, preferably 1 to 4% by volume of water. About 2.3% by volume is used with n-butanol

The flunisolide solution can be obtained in various ways. Any polymorphic form of flunisolide can be added to the alkanol or this can be added to the crystalline form and stirred until the flunisolide is completely dissolved. Then the desired amount of water can be added. However, aqueous alkanol can also be used to prepare the solution. To speed up the process of dissolution, the alkanol can be heated to a temperature of 75 ° C or more up to its boiling point (eg 117 ° C for n-butanol). The alkanol can also be added to an existing solution of flunisolide in a different solvent with a lower boiling point than the alkanol. So z. B. n-butanol is added to a solution of flunisolide in methylene chloride and the methylene chloride is distilled off, the i-butanol being the solvent for flunisolide. This is done by exchange distillation. Of course, it is important to use enough alkanol to keep the flunisolide in solution. Then water is added. Thus the concentration of flunisolide varies with the alkanol used. It has been found that about 50 g of flunisolide at 8O ⁰ C contains in 250ml of n-butanol containing 2% (VoIVVoI.) Water, dissolve and crystallize out of solution and at about 3VC provide the novel crystalline form A.

If the flunisolide has dissolved in the alkanol, then the crystallization of the flunisolide takes place, preferably at a temperature below about 7.5 ° G. This can, for example, done by slowly adding an n-butanol solution, e.g. at a speed of 1 ° C every 30 seconds Let cool down for about 10 minutes. The initial temperature the aqueous alkanol solution can between

• about 30 ⁰ C to about the boiling point of the alkanol.

Although the desired form A of flunisolide is obtained by crystallization only by cooling, this process may not always be economical because a large amount of flunisolide remains in the solution On a small scale, a suitable alkane solvent in which flunisolide is sparingly soluble can be the Alkanol solution can be added to precipitate the flunisolide from the solution. The alkane solvent is preferably η-hexane or n-heptane. Usually there is. added η-hexane or n-heptane volume about two to five times the volume of the alkanol solution and becomes the alkanol solution which is about Contains 50 g of flunisolide for a long time, e.g. B. about 10 minutes to 4 hours or more, slowly added, depending on the volume of the particular solvent depends. So z. B. 750 ml η-hexane to about 250 ml an aqueous n-butanol-FIunisolidlösung within an hour can be added. The alkane solvent may be the same or a lower temperature as that n-butanol solution, but is preferably at room temperature, i.e. about 20 to 25 ° C, to speed up crystallization.

After precipitation of the steroid crystals they will turn into known way, e.g. By vacuum drying, dried to remove any solvent; this can be done for a period of 2 hours to a few days.

The unique crystalline structure of flunisolide with the X-ray diffraction pattern from Table A can be of other polymorphic forms of funisolids e.g. B. by analysis using X-ray powder refraction, differential scanning calorimetry. A distinction can be made between microscopy with polarized light, water analysis and microscopy in a hot state.

The following examples illustrate the present invention.

example 1

50 g of moist flunisolide (with about 1% by weight water content) were placed in a 1-1 ErIenmeyer flask equipped with a magnetic stirrer, and 250 ml of n-butanol containing about 0.1% by volume of water were added , added. The mixture was heated to volbtändigen dissolving at 70 ⁰ C, then the solution was at approximately allowed to cool slowly min l ° C /. Crystallization occurred at about 35 ° C., and at 30 ^° C. n-heptane was slowly added within about 1 hour to a total volume of the mixture of 1 l. After stirring for a further 1 hour at room temperature, the product was filtered several times Washed with n-heptane and air-dried.Then it was dried in a vacuum oven at 50 ^° C. for 3 days and yielded 45 g of flunisolide with the powder X-ray diffraction pattern listed in Table A.

The analysis of the crystals with Karl Fischer reagent in the Aquatest IV from Photovolt showed 1.93% Water.

Example 2

100 g of flunisolide were placed in a 500 ml Erlemeyep flask equipped with a magnetic stirrer, and there were 196 ml of n-butanol for analytical purposes and 4 ml dist. Water added. The mixture was stirred at 95 ° C. until it had completely dissolved heated and cooled in it while stirring. At about 70 ° C crystallization was evident. The received Aufschlänv The mixture was cooled to room temperature and stirred overnight. The product was then nitrated! and air-dried It yielded 85 g of flunisolide with the powder X-ray breakdown pattern listed in Table A.

Analysis of the crystals obtained with Karl Fischer reagent in the aquatest above gave 1.93% water.

Example 3

10 g of flunisolide were introduced into a 50 ml Erlenmeyer flask fitted with a magnetic stirrer, and 15 ml of n-propanol plus 0.6 ml of distilled water were added ⁰ C, then cooled with stirring. The crystallization appeared at about 60 ⁰ 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 give 8.6 g of flunisolide with the powder X-ray diffraction pattern shown in Table A.

Analysis of the crystals with Ksrl-Fischer reagent in the Aquatest IV above gave 2.08 wt% water.

Example 4

10 g of flunisolide were placed in a 50 ml ErIenmeyer flask equipped with a magnetic stirrer, and 20 ml of isopropyl alcohol and 1 ml of distilled water were added. Water was added This mixture was heated to obtain a clear solution to about 70 ° C and then cooled with stirring, the crystallization was found at 50 to 60 ⁰ C. The resulting slurry was cooled to room temperature and stirred overnight. After standing at room temperature for a day, filtering, drying and vacuum drying at room temperature for 24 hours, 8.5 g of flunisolide with the powder X-ray diffraction pattern shown in Table A were obtained.

The analysis of the crystals with Karl Fischer reagent in the above Aquatest IV showed 2.18% water.

Example 5
(Comparison test)

2 g of flunisolide with the X-ray diffraction pattern mentioned in Taoelle A were in a 10 ml Flask containing 95% ethanol introduced at room temperature; the mixture was stirred heated until the material has completely dissolved and the resulting solution then to room temperature cooled, the sides of the flask rubbed with a glass rod to initiate crystallization became. The obtained crystals were analyzed by polarized light microscopy and proved to be different from the originally used flunisolide.

Example 6
(Comparison test)

Example 5 was repeated, with the crystallization by inoculating with a small amount of flunisolide with the Röritgen-Brechüngsmü * mentioned in Table A sters was initiated. The crystals thus obtained were examined by polarized light microscopy analyzed and found to be different from the flunisolide used as seed crystals.

60

Example 7
(Comparison test)

50 g of flunisolide were added to 600 ml of methanol and heated and dissolved to dissolve all of the flunisolide then left to cool. The volume of the resulting solution was increased on a rotary evaporator Half, then the resulting slurry was filtered and the crystalline flunisolide isolated. That The filtrate was again evaporated to a volume of about 60 ml and then filtered again as above. That The material obtained was air-dried and gave 26 g of flunisolide, which (according to analysis by X-ray diffractometry, Differential Scanning Calofimetry, Visual Thermal Analysis, And Weight Loss On Heating of 2.6%) differed from the TV material with the X-ray diffraction pattern specified in Table A.

Example 8
(Vergieicnsversucn)

100 mg of flunisolide were in 20 ml of abs. Dissolved ethanol at about 70 ^° C., the solution obtained was cooled to room temperature and allowed to evaporate for 3 days and the crystalline flunisolide obtained was collected, by X-ray diffractometry, differential scanning calorimetry, visual thermal analysis and weight loss on heating (4,5,4, 9%) analyzed. It was found to differ from crystalline flunisolide with the X-ray diffraction pattern shown in Table A.

Example 9

10 g of flunisolide was placed in a 50 ml Erlenmeyer flask fitted with magnetic stirring and 20 ml of tert-butyl alcohol and 1 ml of dist. V / ater added. The mixture was heated until a clear solution was obtained and then cooled with stirring, until crystallization showed. The resulting slurry was cooled to room temperature and stirred overnight, filtered, air-dried and vacuum-dried at room temperature for 24 hours. whereby flunisolide having the powder X-ray diffraction pattern shown in Table A was obtained.

Analysis of the crystals with Karl Fischer reagent in the Aquatest IV above showed about 2% by weight of water.

Claims (1)

Palent claim: Process for producing a crystalline form of flunisolide (6a-fluorine-11 ^ 1-dihydroxy-16o, 17a.-isopropylidene-dioxypregna-1,4-diene-3,20-dione) with a water content of 2.0 ± 0.2% by weight and the following X-ray diffraction pattern: