DE3019250A1 - METHOD FOR PRODUCING A CRYSTALLINE SHAPE OF FLUNISOLIDE - Google Patents

Description

PATENT LAWYERS

Dipl.-Ing. P. WIRTH Dr. V. SCHMIED-KOWARZIK Dipl, lng. G. DANNENBERG Dr. P. WEINHOLD Dr. D. GUDEL

335024 SIEGFRIEDSTRASSE 8

^{TELEPHONE: CO895} 335025 8000 MONKS

SK / SK / St Caeat 19270

SYNTEX CORPORATION

Bank of America 3401 Hillview Avenue

Ninth Floor, CaIIe 50 Palo Alto, California Panama 94304

Republic of Panama USA

Process for producing a crystalline form of Flunieolide

0300A9 / 079.2

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The present invention relates to a method for the production of a unique, crystalline form of Flunisolid (hereinafter referred to as Form A).

In the USA, flunisolide is the common name for OCX-Fluoric ß, 21 -dihydroxy-16c *, 1 ytf-isopropylidenedioxy-pregna-i, 4-diene 3,20-dione. The class of compounds to which flunisolide and methods of making them are described in US Pat

ίο 3 126 575 described. These compounds show anti-inflammatory properties and antipyretic activity and find particular use in the treatment of local inflammation. Flunisoiid can also be formulated with pharmaceutically acceptable aerosol propellants and used for treatment Respiratory diseases such as asthma, allergic Rhinitis, etc., can be used in humans and animals (see e.g. BE PS 842 192). A special polymorphic form (Form A, a hemihydrate) of the flunisolide has proven to be special in the presence of aerosol propellant formulations has been shown to be stable and is therefore preferred (see the above mentioned BE PS 842 192). However, since flunisolide has the ability to form various polymorphic forms and also May form crystals that contain some of the solvent, from which the product is crystallized, must a process can be applied that is reproducible in Way provides the form A of flunisolide.

_{In US Pat. No. 3,126,375, the solvents Z 9} B * used for crystallizing the steroid family to which flunisolide belongs include ethyl acetate and methanol. Will this

Solvent, however, for recrystallizing Flunisoiid It was found that fluniaolide in general was used © in Clatljrats Solvat or a related solution ■ ffilttelainsclaliaßkösiiplex ("solvent inclusion complex") with äiessn .Solvent forms. These crystal forms of the . ·. - Flunisolii are: unacceptable due to the

Aerosol formulation required linearity

, Q 30049/0792 BAD ORIGINAL

In BE PS 842 192 a process for the production of form A of flunisolide is described. This particular one However, the process uses halogenated hydrocarbons which have certain undesirable properties.

It has now been found that Form A of flunisolide (a Hemihydrate) can be produced in a reproducible manner by the process according to the invention. The procedure is characterized in that flunisolide is obtained from an aqueous solution of an alkanol with 3 or 4 carbon atoms crystallized. 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 Umkristallisation of flunisolide from an aqueous solution of methanol or Ethanol does not receive Form A.

The unique crystalline form of flunisolide produced according to the invention is a hemihydrate crystal \ n \ ertes flunisolide, namely eri-fluorine-iiß ^ i-dihydroxy-ieoc / lTrf-isopropylidene-dioxypregna-1,4-diene-3,20-dione, and is referred to as Form A in the following. The crystalline structure has a powder X-ray diffraction pattern according to the following Table A.

In the following table means

b = broad line because two are close together Lines cannot be separated konatea

Q30048 / 0782 BATH ORIGINAL

d - X. - 50 Q ο Table A. 60 5 A. 1 / I ₁ 80 deg. 04/10 50 4.4 9.82 * 50 4.5 9.30 10 4.8 7.69 90 5.8 10 6.91 100 6.4 6.32 60 7.0 5.98 60 7.4 5.53 10 8.0 5.21 70 8.5 5.06 1 8.8 4.79 10 9.3 15th 4.55 10 9.8 4.33 ⁵ b 10.3 4.13 5 10.8 3.95 10 11.3. 3.86 1 11.5 3.70 2 12.0 3.63 2. 12.3 3.36 1 13.3 20th 3.30 2 13.5 3.21 2κ 13.9 3.03 1 14.8 2.88 1 15.5 2.67 1 16.8 2.63 3 17.0 2.60 1 17.3 2.56 1 17.5 25th 2.40 1 18.8 2.31 1 19.5 2.28 1 19.8 2.13 2 21.3 2.10 21.5 1.97 23.0 1.88 24.3 30th 35
■ ..

0300A9 / 0792

A general discussion of theory and definitions and the general method of X-ray diffractometry can be found on pages 902 to 904 of the National Formulary, XIII.

The above X-ray diffraction pattern "was obtained by the method of BE-PS 842 192.

Form A of flunisolide can be further characterized by the presence of 2.0 + 0.2% 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.

Analysis of Form A for water content is carried out by any suitable analytical method, generally using a Karl Fischer reagent. The Karl Fischer analysis on water can be carried out according to the original method in Angew.

Chemie 48, 394 (1935); however, it is preferably measured using the Aquatest IV automatic analyzer from Photovolt Corp. carried out. The Aquatest IV device is a coulometric titrator that introduces microprocessor control and is based on the specific and quantitative reaction of water with the Karl Fischer reagent. The instrument is unique in that the reagent is generated electronically, eliminating the need for standardization or calibration. The accuracy of the instrument is within +10 micrograms (meg) or 1 % (whichever is greater. 1st). For the determination of water in form A of flunisolide, the sample sizes chosen for the determination were between 35 and 75 mg and contained between 700 and 1500 meg of water; the accuracy was within + 0.03 % of the amount of water, determined in meg.

0300A9 / 0 7 92

The microprocessor control is used to distinguish between the titration water present in the sample and any reaction of the Karl Fischer reagent with others Compounds such as aldehydes or ketones. The Aquatest IV is carried out according to the instruction manual of Photovolt Corp. dated July 1978 and according to publication No. 260, submitted at of 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 device used for Flünisolidkristallisätion is complete is clean. Is in the flask or container to carry out the crystallization another polymorphic form of the Flunisoüds present, then the desired form A with a other phase may be contaminated at the same time due to the crystallization caused by the present crystals of flunisolide are formed. Before performing the The method according to the invention, it is therefore expedient to use the Wash the device thoroughly with the alkanol to be used, e.g. aqueous n-butanol, in order to remove it, that any other flunisolide of a different crystal form is completely removed from it.

As mentioned above, the method of the invention is thereby characterized in that one flunisolide from an aqueous solution of an alkanol with 3 or 4 carbon atoms crystallized. Alcohols with 3 or 4 carbon atoms include, for example, isopropyl alcohol> n-propanol, n-butanol, isobutyl alcohol, sec►-butyl alcohol, tert-butyl alcohol, whereby n-butanol is preferred, The alkanol is aqueous, i.e. it contains about 0.2 to 5 Vol .-! & Water, preferably 1 to 4 vol .-% water. With About 2.3% by volume of n ^ butanol are used.

The flunisolide solution can be obtained in several ways will. 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. Thereafter

030049/0792

the desired amount of water can be added. However, aqueous alkanol can also be used to prepare the solution. In order to accelerate the process of dissolving, 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. For example, n-butanol can be added to a solution of flunisolide in methylene chloride and the methylene chloride can be distilled off, the n-butanol becoming 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 will vary with the alkanol used. It has been found that about 50 g of flunisolide at 80 ⁰ C contains up in 250 ml of n-butanol containing 2% (Vol./VoI^ water, dissolve and from the solution at 35 ° C ^wa et crystallize and the new crystalline form of A deliver.

If the flunisolide has dissolved in the alkanol, then the crystallization of the flunisolide takes place, preferably at a temperature below about 75 ^° C. This can be seen, for example, by adding an n-butanol solution slowly, for example at a rate of 1 ^° C. every 30 seconds Let cool for about 10 minutes. The initial temperature of the aqueous alkanol solution can be between

point of the alkanol liqgen.

Alkanol solution can be between about 30 ⁰ C to about the boiling point

Although the desired form A of flunisolide is through crystallization obtained only by cooling, this method cannot always be economical because of a large amount Flunisolide remains in the solution. On a small scale, a suitable alkane solvent in which flunisolide is sparingly soluble, can be added to the alkanol solution in order to precipitate the flunisolide out of the solution.

030049/0792

_ήή 301925Q

■■ * ^ s -

is preferably η-hexane or n-heptane. Usually the added volume of η-hexane or n-heptane is about two to five times the volume of the alkanol solution and is slowly added to the alkanol solution, which contains about 50 g of flunisolide, over a longer period of time, e.g. about 10 minutes to 4 hours or more, which depends on the volume of the respective solvent. For example, 750 ml of η-hexane can be added to about 250 ml of an aqueous n-butanol-flunisolide solution within one hour. The alkane solvent can have the same or a lower temperature as the n-butanol solution, but is preferably at room temperature, ie about 20 to 25 ^° C., in order to accelerate the crystallization.

After the steroid crystals have precipitated, they are dried in a known manner, e.g. by vacuum drying, in order to remove any Remove 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 of Table A can differ from others polymorphic forms of funisolids e.g. by analysis using X-ray powder refraction, differential scanning calorimetry, Polarized light microscopy, water analysis and micro hot copy.

The following examples illustrate the present Invention.

Example 1 \

50 g moist flunisolide (with about 1% by weight water content) were placed in a 1 to 1 Erlenmeyer flask fitted with a magnetic stirrer and 250 ml of n-butanol containing about 0.1% by volume of water were added. The mixture

^{“Was heated to 70 °} C. until it was completely dissolved, then the solution was allowed to cool at about 1 ° C./minute. At about 35 ^° C. a crystallisetion appeared, and at 30 ^° C.

0300A9 / 0792

was slowly added n-heptane to a total volume of the mixture of 1 l within about 1 hour. After stirring for a further 1 hour at room temperature, the product was filtered, washed several times with n-heptane and air-dried. Then it was dried in a vacuum oven at 5O ⁰ C for 3 days dried to provide 45 g of flunisolide with listed in Table A powder X-ray diffraction pattern.

ίο 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 590 ml Erlenmeyer flask equipped with a magnetic stirrer, and 196 ml of n-butanol for analytical purposes and 4 ml of distilled water were added. Water added. The mixture was heated to 95 ° C. with stirring until completely dissolved and then cooled with stirring. At about 70 ^° C. the crystallization was evident. The resulting slurry was cooled to room temperature and stirred overnight. Then the product was filtered and air dried. It provided 85 g of flunisolide with the powder X-ray diffraction pattern shown in Table A.

The analysis of the crystals obtained with Karl Fischer reagent in the above Aquatest showed 1.95 % water.

Example 3.

10 g of flunisolide were introduced into a 50 ml Erlenmeyer flask equipped with a magnetic stirrer, and 15 ml of n-propanol plus 0.6 ml of distilled water were added. Water added. ^{The mixture was heated to 90 °} C. with stirring until it had completely dissolved, then cooled with stirring. The crystallization appeared at about 60 ^° C., and the resulting slurry was cooled to room temperature with stirring - refraction pattern.

Q30049 / 0792

The analysis of the crystals with Karl Fischer reagent in the above Aqüatest IV showed 2.08 wt -.% Water. Example A

10 g of flunisolide were placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer, and 20 ml of isqpropyl alcohol and 1 ml of distilled water were added. Water added. ^{This mixture was heated to about 70 °} C. until a clear solution was obtained and then cooled with stirring. The crystallization showed up at 50 to 60 ^° C. The resulting slurry was cooled to room temperature and stirred overnight. After standing for 6 days at room temperature, filtering, air 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.

Analysis of the crystals with Karl Fischer reagent in the above Aqüatest IV showed 2.18 % water.
Beds ρ i el 5

20-2 g of flünisolide with the X-ray diffraction pattern given in Table A. were placed in a flask containing 10 ml of 95% ethanol at room temperature; the mixture was stirred until the Material heated and the resulting solution then cooled to room temperature, with the sides of the flask with rubbed a glass rod to initiate crystallization. The obtained crystals were examined by microscopy analyzed with polarized light and found to be different from the originally used flünisolide.

B e is ρ ie I 6

Example 5 was repeated, the crystallization being carried out by seeding a small amount of flunisolide with that in Table A called X-ray diffraction pattern was initiated. The crystals obtained in this way were examined by microscopy with polar

“'Ized light analyzed and found to be different of the flunisolide used as seed crystals.

030049/0792

Example 7

50 g of flunisolide were added to 600 ml of methanol and heated to dissolve all of the flunisolide and then cool calmly. The volume of the resulting solution was reduced by half on a rotary evaporator, then was the resulting slurry is filtered and the crystalline flunisolide is isolated. The filtrate was again on a Volume of about 60 ml evaporated and then again like filtered above. The material obtained was air-dried and gave 26 g of flunisolide, which (according to analysis X-ray diffractometry, differential scanning calorimetry, visual thermal analysis and weight loss on heating 2.6 #) of material with that listed in Table A. X-ray diffraction pattern differed.

' Example 8

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, differential scanning calorimetry by X-ray diffractometry, 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.

10g of flunisolide were poured into one with magnetic stirring provided with a 50 ml Erlenmeyer flask and 20 ml of tert-butyl alcohol and 1 ml dist. Water added. The mixture was heated until a clear solution was obtained and then cooled with stirring until crystallization appeared. The resulting slurry was at room temperature cooled 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.

The analysis of the crystals with Karl Fischer reagent in the above Aquatest IV to give about 2 wt -.% Water.

030049/0792

Claims (1)

P a te nt a η s ρ r Ü c h e 3019250 50 300A9 / 0792 α 60 deg. ^ - \ Process for the production of a crystalline form of 80 ^ FjLunisolide (6tf-fluoro-11 ß, 21 -dihydroxy-16 ü, 17Λ -isopropylidene- 50 4.4 dioxypregnä-T, 4-diene-3 50 4.5 5 2.0 + 0.2! Wt. % And the
-.-- ". ■ - - - 10 4.8 : -: - "■■■; - ■. D,. 90 5.8 100 6.4 10 60 7.0 10.04 '"■ 60 7.4 9.82 10 8.0 9.30 70 8.5 7.69 ι · 8.8 6.91 10 9.3 6.32 10 9.8 15th 5.98 5b 10.3 5.53 5 10.8 5.21 10 11.3. 5.06 1 11.5 4.79 2 12.0 4.55 2 12.3 4.33 1 13.3 4.13 2 13.5 20th ; 3.95 ² D 13.9 3.86 1 14.8 3.70 1 15.5 3.63 1 16.8 3.36 3 17.0 3.30 1 17.3 3.21 1 17.5 25th 3.03 1 18.8 2.88 1 19.5 2.67 1 19.8 2.63 2 21.3 2.60 that you can get the steroid 21.5 2v56 Solution in a liquid alkanol with 3 or 23.0 2.40 atoms, which contains 0.2 to 5 % by volume of water, 24.3 2.31 - ■ - -
Q from his 30th 2.28 '4 carbon 2.13 crystallized. 2.10 1.97 1.88 characterized, 35 , 20-dione) with a water content of the following X-ray refraction patterns: 1 / I ₁ % 2.- Procedure according to - 2 -
Claim 1, characterized in that contains. Claim 1 and 2, characterized by Procedure according to Claim 1 to 4, marked by this Procedure according to Claim 1 to 5, marked by this and the following X-ray diffraction pattern 50 O the Solution 1 to 4 V0I.-96 water 2, characterized by that the alkanol is isopropyl alcohol or n-propyl alcohol that the alkanol solution from a temperature above that the solution ■ reduced to a temperature below 30 ⁰ C 1 / I ₁ 60 deg. 5 3.- Procedure according to Claim 1 and that the alkanol is n-butanol. • 75 ⁰ C to a temperature below 75 * was cooled. % 80 4.4 net Procedure according to ³ C, at which the 50 4.5 4.- Crystallization takes place, is allowed to cool. 7.- 50 4.8 net 6.- from 10 5.8 10 is net, Crystalline form of flunisolide with a water content 90 6.4 5.- 2.0 + 0.2 wt. 96 100 7.0 net d 60 7.4 O
A. 60 8.0 15th 04/10 10 8.5 9.82 70 8.8 9.30 1 9.3 7.69 10 9.8 20th 6.91 10 10.3 6.32 ⁵ b 10.8 5.98 5 ^D 11.3. nt 5.53 10 11.5 5.21 12.0 5.06 12.3 4.79 4.55 30th 4.33 4.13 3.95 3.86 3.70 3.63 35 030049/0792 1 / I ₁ A% deg. 3.36 3.30 3.21 3.03 2.88 ίο 2.67 2.63 2.60 2.56 2.40 2.31 2.28 2.13 2.10 1.97 1.88 1 13.3 2 13.5 2 13.9 1 14.8 2 15.5 ² b 16.8 1 17.0 1 17.3 1 17.5 3 18.8 1 19.5 1 19.8 1 21.3 1 21.5 1 23.0 2 24.3 obtainable by a process according to claims 1 to 6. The patent attorney (Dr ViSchaied-Kowarzilc) 0 3 004 9/0792