DK162530B - PROCEDURE FOR PREPARING A CRYSTALLINE MODIFICATION OF FLUNISOLIDE - Google Patents

Description

DK 162530 B

The invention relates to a particular process for preparing a crystal form of flunisolide (hereinafter Form A), as set forth in the preamble of claim 1, by crystallizing the flunisolide from a solvent.

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Flunisolid is the generic name for 6α-fluoro-11α, 21-dihydroxy-16α, 17α-isopropylidene dioxypregna-1,4-diene-3,20-dione. The class of compounds to which flunisolid belongs and processes for their preparation are described in U.S. Patent No. 3,126,375. These compounds exhibit anti-inflammatory and antipyretic action and are primarily used in the treatment of topical inflammation. Flunisolid can also be prepared with pharmaceutically acceptable aerosol propellants and used in the treatment of respiratory disorders such as asthma, allergic rhinitis etc. in mammals (see, for example, Belgian Patent Specification No. 842,192). A particular polymorphic form (Form A, a hemihydrate) of flunisolid has been found to be particularly stable in the presence of aerosol propellant formulations and is therefore preferred (see the aforementioned Belgian Patent Specification No. 842,192).

Due to the ability of flunisolide to form various polymorphic forms as well as to form crystal constitutions which include some of the solvents from which the product is crystallized, a method which reproducibly yields the desired Form A of flunisolide must be used.

In U.S. Patent No. 3,126,375, solvents used to crystallize the family of steroids to which flunisol belongs include such solvents as e.g. ethyl acetate and methanol. However, when these solvents are used to recrystallize flunisolide, it has been found that flunisolid generally forms a clathrate, solvate or related solvent inclusion complex with these solvents. Such crystal forms of flunisolide are not acceptable due to the uniformity requirement for a pharmaceutically acceptable aerosol formulation.

Belgian Patent No. 842,192 discloses a process for the preparation of Form A of flunisolid. By this one

DK 162530 B

However, in two particular processes halogenated hydrocarbons such as methylene chloride and so-called "Freon" compounds are used. It is known that halogenated hydrocarbons have many undesirable properties which greatly limit their use 5 and cause major safety problems in large scale production using large volumes of solvents. By way of example, "Freon" under high heat can decompose to harmful materials and, moreover, is considered harmful to the environment, as it is associated with ozone degradation in the atmosphere. Carbon tetrachloride is toxic and may also be carcinogenic and methylene chloride is narcotic at high concentrations. The handling of halogenated hydrocarbons used in BE 842.192 therefore presents problems of commercial importance as precautions must be taken in their use. The process of the invention avoids the use of these halogenated hydrocarbons and hence the accompanying safety problems, using alkanol solvents such as e.g. N-butanol.

It has now been found that Form A of flunisole (a hemihydrate) can be reproducibly obtained by the method of the invention. The process relates to the crystallization of flunisolide from an aqueous solution of an alkanol having 3 or 4 carbon atoms and is characterized by the characteristic part of claim 1. The crystals thus formed reproducibly exhibit Form A, crystalline flunisolid. This is surprising, especially given the fact that if one recrystallizes flunisolid from an aqueous solution of methanol or ethanol, Form A.

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The crystal form of flunisolide prepared by the process of the invention is a hemihydrate, crystalline flunisolide, 6a-fluoro-110,21-dihydroxy-16a, 17a-isopropyl-lidendioxypregna-1,4-diene-3,20-dione and is referred to herein as Form 35 a. The crystal structure has a powder X-ray diffraction pattern as set forth in the following Table A.

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Table A

d I / I1 Λ% deg 10.04 50 4.4 5 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 10 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 15 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 20 3.70 5D 12.0 3.63 10 12.3 3.36 1 13.3 3.30 2 13.5 3.21 2 13.9 25 3.03 1 14.8 2.88 2 15.5 2.67 2. 16.8 2.63 1 17.0 2.60 1 17.3 30 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 35 2.10 1 21.5 1.97 1 23.0 1.88 2 24.3 b = Wide line due to failure to split two adjacent lines.

40 A general discussion of the theory and definitions as well as the general method of X-ray diffraction measurement is given in the monograph pages 902-904 of National Formulary, XIII.

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The above X-ray diffraction patterns were obtained according to the method described in Belgian Patent No. 842,192.

Form A of flunisolid is further characterized by the presence 5 of 2.0 + 0.2 wt% water. Because the calculated stoichiometric value of the weight percent of water for a flunisolid hemihydrate is 2.03%, it appears that Form A is a hemihydrate.

Form A water content analysis is done by any suitable analytical method. Generally, 10 is analyzed using Karl Fischer reagent. Karl Fischer analysis for water can be performed according to the original method set forth in Angewandte Chemie, 48, 394 (1935}. However, the analysis is preferably performed using the Photovolt Corporation's automatic analysis apparatus, Aquatest IV. Aquatest IV is a columetrical titration method, which includes microprocessor control and is based on the specific and quantitative reaction of water with Karl Fischer reagent, in particular the electronic formation of the reagent, eliminating the need for standardization or adjustment. For the determination of water in flunisolid Form A, where the sample sizes selected for the provisions are between 35 mg and 75 mg and contain between 700 mcg and 1500 mcg of water, there is 25 micrograms (mcg) or 1%, whichever is greater. the accuracy within + 0.03% of the amount of water determined in mcg.

The microprocessor control serves to distinguish between the titration of water present in the sample and any reaction of the Karl Fischer reagent with other entities such as aldehydes or ketones. Aquatest IV is performed as described in the instruction manual published by Photovolt Corporation in July 1978 and with the help of K.A. Lindblom's Paper No. 260, presented in February 1978 at the Pittsburg Conference on Analytical Chemistry and Applied Spectroscopy. The address of the Photovolt Corporation is 1115 Broadway, New York, New 35 York 10010.

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In the process of the invention, it is important that the equipment used for the crystallization of flunisolid is perfectly pure. If in the flask or container in which the crystallization takes place, another polymorphic form of flunisolide is found, the desired Form A may be contaminated with another of the phases formed simultaneously, due to the crystallization controlled by the existing crystals of flunisolid. Thus, prior to carrying out the process of the invention, it is wise to wash all equipment carefully with the alkanol to be used, e.g. aqueous n-butanol to ensure that any unauthorized flunisolid of another crystal form is completely removed from the equipment.

As previously pointed out, the process of the invention relates to crystallization of flunisolid from an aqueous solution of an alkanol having 3 or 4 carbon atoms. Alkanols having 3 or 4 carbon atoms are isopropyl alcohol, n-propanol, n-butanol, iso-butyl alcohol, sec-butyl alcohol and tert-butyl alcohol. n-butanol is preferred. The alkanol is aqueous and contains 0.2-5 volume% water, preferably 1-4 volume * water. In particular, the n-butanol contains approx. 2.3 volume * water.

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 crystal form of flunisolide and stirred until the flunisolide is completely dissolved. Then the desired amount of water can be added. However, for the preparation of the solution, aqueous alkanol can also be used. To . To accelerate the dissolution process, the alkanol can be heated to a temperature of 75 ° C or more to its boiling point (e.g., 117 ° C for n-butanol). Alternatively, the alkanol can be added to an existing solution of flunisolid in another solvent having a lower boiling point than the alkanol. n-butanol can e.g. is added to a solution of flunisolide in methylene chloride and the methylene chloride is distilled off while n-butanol becomes the solvent for flunisolide. This is done by substitution distillation. Of course, it is important to apply

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6 sufficient alkanol to keep the flunisolide in solution. Then add water. The concentration of flunisolid will vary with the alkanol used. It has been found that approx. 50 g of flunisolide at 80 ° C will dissolve in 250 ml of n-butanol containing 2% v / v water and crystallize from the solution at ca. 35 ° C to give crystal form A.

Once the solution of flunisolide in the alkanol has been obtained, the crystallization of crystal form A of the flunisolide 10 is preferably effected at a temperature of less than ca. 75EC. This can be done, for example. be done by allowing an n-butanol solution to cool slowly, e.g. at a rate of 1 ° every 30 seconds to approx. 10 minutes. The initial temperature of the aqueous alkanol solution may be anywhere between ca. 30 ° C to about the boiling point of the alkanol.

Although the desired Form A of flunisolide is obtained by allowing crystallization by cooling alone, such a process is not always economically advantageous due to the large amount of flunisolide remaining in solution. On a small scale, a suitable alkane solvent (in which flunisolide has poor solubility) can be added to the alkanol solution to force the flunisolide out of the solution. The alkane solvent is preferably n-hexane or n-heptane. The n-hexane or n-heptane volume commonly added is approx. 2 to approx. 5 times the volume of the alkanol solution and slowly add to the alkanol solution containing approx. 50 g flunisolide over a longer period, e.g. ca. 10 minutes to 4 hours or more, depending on the volumes of the solvents involved. For example, add 750 ml of n-hexane to ca. 250 ml of an aqueous n-butanol flunisolide solution over one hour. The alkane solvent may have the same temperature as the n-butanol solution or a lower temperature, but preferably has room temperature, i.e. ca. 20-25 ° C, to promote crystallization.

When the steroid crystals are obtained, they are dried in a known manner, such as by vacuum drying to remove any dissolving solution.

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7 remedy. This can happen for a period of 2 hours to several days.

The unique crystal structure of flunisolid with the X-ray diffraction pattern shown in Table A 5 can be distinguished from other polymorphic forms of flunisolid using, among others, X-ray powder diffraction analysis, differential scanning geometry, polarized light microscopy, water analysis and hot-stage microscopy.

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The following Examples 1-4 and 9 further illustrate the process of the invention, while Examples 5-8 are comparative in Examples.

Example 1 50 g of moist flunisolide (containing about 1% by weight water) is placed in a 1 liter Erlenmeyer flask equipped with magnetic stirring, and 250 ml of n-butanol containing approx. 0.1 volume * of water 20 is added. The mixture is heated to 70 ° C until complete dissolution is obtained and then the solution is allowed to cool slowly with approx. 1 ° pr. minute. At about. At 35 ° C the crystallization becomes visible and at 30 ° C n-heptane is slowly added over a period of approx. 1 hour until the total volume of the mixture is 1 liter. After stirring for another hour at ambient temperature, the product is filtered and washed several times with n-heptane and air dried. The substance is then dried in a vacuum oven at 50 ° C for 3 days to obtain 45 g of flunisolid with a powder X-ray diffraction pattern as set forth in Table A.

Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV yields 1.93% water.

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Example 2 100 g of flunisolide are placed in a 500 ml Erlenmeyer flask equipped with magnetic stirring and 196 ml of analytical grade n-butanol and 4 ml of distilled water are added. The mixture is heated to 95 ° C with stirring until complete solution is obtained and then cooled with stirring. At about. At 70 ° C the crystallization becomes visible. The resulting slurry is cooled to room temperature and stirred overnight. The product is then filtered and air dried to give 85 g of flunisolid with the powder X-ray diffraction coins listed in Table A.

Analysis of the resulting crystals using Karl Fischer reagent in Photovolt's Aquatest yields 1.93 wt.

Example 3 10 g of flunisolide is placed in a 50 ml Erlenmeyer flask equipped with magnetic stirring and 15 ml of n-propanol plus 0.6 ml of distilled water are added. The mixture is heated to 90 ° C with stirring until complete dissolution is obtained and then cooled with stirring. Crystallization appears at ca. 60 ° C and the resulting slurry is cooled with stirring to room temperature. After stirring overnight at room temperature, the product is filtered and air dried to give 8.6 g of flunisolide with the powder X-ray diffraction pattern set forth in Table A.

Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV yields 2.08 wt% water.

Example 4 10 g of flunisolide is placed in a 50 ml Erlenmeyer flask equipped with magnetic stirring and 20 ml of isopropyl alcohol and 1 ml of distilled water are added. The mixture is heated to ca. 70 ° C until a clear solution is obtained. Then cool below

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9 stirring. The crystallization becomes visible at 50-60 ° C. The resulting slurry is cooled at room temperature and stirred overnight. After standing for 6 days at room temperature, filtering, air drying and drying in vacuo at room temperature for 24 hours, 8.5 g of flunisolide is obtained with the powder X-ray diffraction pattern set out in Table A.

Analysis of the crystals using Karl Fischer reagent in Photovolt's Aquatest IV yields 2.18% water.

Example 5 10 2 g of flunisolide with the X-ray diffraction pattern set out in Table A are added to a flask containing 10 ml of 95% ethanol at room temperature. The mixture is heated with stirring until all material has completely dissolved. The resulting solution is then allowed to cool to room temperature while rubbing the sides of the flask with a glass rod to produce crystallization. The obtained crystals were analyzed using polarized light microscopy and found to be different from the flunisolid initially used.

Example 6 The procedure of Example 5 was repeated except that the crystallization was induced by grafting a small amount of flunisolid with the X-ray diffraction pattern set out in Table A. The resulting crystals thus obtained were analyzed using polarized light microscopy and were found to be different from the flunisolide used as seed crystals.

Example 7 50 g of flunisolide was added to 600 ml of methanol and heated to dissolve the entire flunisolide amount. Cooling is then allowed.

The volume of the resulting solution was reduced to half on a rotary evaporator and the resulting

DK 162530 B

Ten slurries were then filtered and crystalline flunisolide isolated. The filtrate was again evaporated to a volume of ca.

60 ml and then filtered again as above. The resulting substance was air dried, yielding 26 g of flunisolid, which (analyzed via X-ray diffractometry, differential scanning calorimetry, visual heat analysis and weight loss at heating of 2.6%) was different from that of Table A. X-ray diffraction.

Example 8 100 mg of flunisolide was dissolved in 20 ml of absolute ethanol at ca.

70 ° C. The resulting solution was cooled to room temperature and allowed to evaporate over a 3-day period.

The resulting crystalline flunisolide was collected, analyzed by X-ray diffractometry, differential scanning calometry, visual heat analysis and weight loss on heating (4.5, 4.9%). The resulting crystalline flunisolide was found to be different from the crystalline flunisolide which exhibits the X-ray diffraction pattern set out in Table A.

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EXAMPLE 9 20 g of flunisolide is placed in a 50 ml Erlenmeyer flask equipped with magnetic stirring and 20 ml of t-butyl alcohol and 1 ml of distilled water are added. The mixture is heated until a clear solution is obtained, then cooled with stirring until crystallization becomes visible. 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 obtain flunisolid with the powder X-ray diffraction pattern set out in Table A.

Analysis of the crystals using Karl Fischer reagent in Photovolt's Aqua test IV yields approx. 2% by weight water.

Claims (6)

A process for preparing a crystalline form of flunisolid containing 2.0 ± 0.2% by weight of water and exhibiting an X-ray diffraction pattern as set forth in Table A Table A Process according to claim 1, characterized in that said solution contains 1-4 volume% water. Process according to claim 1 or 2, characterized in that the alkanol is n-butanol. Process according to claim 1 or 2, characterized in that the alkanol is isopropyl alcohol or n-propyl alcohol. 15 Process according to claim 1 or 2, characterized in that said alkanol solution is allowed to cool from a temperature above 75 ° C to a temperature below 75 ° C at which crystallization takes place. 20 5. I / J ^ Θ Å. % deg. 10.04 50 4.4 9.82 60 4.5 9.30 80 4.8 10 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 15 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 20 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 25 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 30 2.67 2. 16.8 2.63 1 17.0 2.60 1 17.3 2.56 1 17.5 2.40 3 18.8 35 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 40 1.88 2 24.3 DK T6253OB by crystallizing the flunisolide from a solvent, characterized in that a solvent is used as a solvent. liquid alkanol with 3 or 4 carbon atoms containing 0.2-5% by volume water. 5 Process according to any one of the preceding claims, characterized in that said solution is cooled to a temperature below 30 ° C. 25 30 35