CH643567A5 - METHOD FOR PRODUCING A CRYSTALLINE SHAPE OF FLUNISOLIDE. - Google Patents

Description

The present invention relates to a process for the production of a crystalline form of flunisolide, which is referred to below as Form A.

Flunisolide is the final international free name for 6a-fluoro-lß, 21-dihydroxy-16ct, 17a-isopropylidendioxypregna-1,4-diene-3,20-dione. The class of compounds to which flunisolide belongs and methods of making such compounds are described in U.S. Patent No. 3,126,375 to Ringold et al. described. These compounds show anti-inflammatory and antipyretic activity and are primarily used in the treatment of local inflammation. Flunisolide can also be formulated with pharmaceutically acceptable aerosol propellants and used to treat respiratory complaints such as asthma, allergic rhinitis, etc. in humans and mammals (see e.g. BE-PS No. 842 192). A special polymorphic form (form

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

643567

A, a hemihydrate) of flunisolide has proven to be particularly stable in the presence of aerosol propellant formulations and is therefore preferred (see BE-PS No. 842 192 mentioned above). However, since flunisolide can form various polymorphic forms and can form crystal habituses that contain some of the solvents from which the product has been crystallized. a method must be used which gives the desired form A of flunisolide in a reproducible manner.

In U.S. Patent 3,126,375 to Ringold et al. are used as solvents for crystallization for the class of steroids to which flunisolide belongs, solvents such as ethyl acetate and methanol. However, when these solvents are used to recrystallize flunisolide, it is found that flunisolide generally forms a cage compound, a solvate, or a related solvent inclusion complex with these solvents. Such crystal forms of flunisolide are not acceptable because a pharmaceutically acceptable aerosol formulation must be uniform.

BE-PS No. 842 192 describes a process for the production of Form A of flunisolide. However, this particular process uses halogenated hydrocarbons that have some undesirable properties.

It has now been found that form A of flunisolide (a hemihydrate) can be obtained in a reproducible manner by means of the process according to the invention. The process is characterized in that flunisolide is crystallized from an aqueous solution of an alkanol having 3 or 4 carbon atoms. The crystals formed in this way reproducibly show the form A of crystalline flunisolide. This is surprising, in particular in view of the fact that form A is not obtained when flunisolide is recrystallized from an aqueous solution in methanol or ethanol.

The unique crystalline form of flunisolide, which is produced by the process according to the invention, is a crystalline flunisolide hemihydrate, i.e. a crystalline hemihydrate of 6a-fluoro-1ß, 21-dihydroxy-16a, 17a-isopro-pylidendioxypregna-l, 4-diene-3,20-dione, and is referred to as Form A hereinafter. This crystalline product has the Debye-Scherrer diagram shown in Table A below.

Table A

there

I / Ii

0 / O

0

Degree

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

10th

7.0

5.98

90

7.4

5.53

100

8.0

5.21

60

8.5

5.06

60

8.8

4.79

10th

9.3

4.55

70

9.8

4.33

1

10.3

4.13

10th

10.8

3.95

10th

11.3

3.86

5b

11.5

3.70

5

12.0

3.63

10th

12.3

3.36

1

13.3

Table A (continued)

d r / ii

0

Â

%

Degree

3.30

2nd

13.5

3.21

2nd

13.9

3.03

1

14.8

2.88

2nd

15.5

2.67

2 B

16.8

2.63

1

17.0

2.60

1

17.3

2.56

1

17.5

2.40

3rd

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

2nd

24.3

b = wide line because two closely adjacent lines have not been resolved.

A general discussion of the theory, definitions, and general procedures for taking X-ray diffraction patterns is provided in the monograph on pages 902 to 904 of National Formulary XIII.

The above X-ray diffraction pattern was obtained by the method described in BE-PS No. 842 192.

Form A of flunisolide is further characterized in that it contains 2.0 ± 0.2% by weight of water. Since the calculated stoichiometric water content for a hemihydrate of flunisolide is 2.03% by weight, it follows that Form A is a hemihydrate.

Form A can be analyzed for water content by any suitable analytical method. The Karl Fischer reagent is generally used for the analysis. The Karl Fischer analysis on water can be carried out according to the original method set out in Angewandte Chemie 48, 394 (1935). However, the analysis is preferably carried out using an automatic analysis device from Photovolt Corporation, which is referred to as Aquatest IV. It is a coulometric titration device controlled by microprocessors and based on the specific and quantitative reaction of water with the Karl Fischer reagent. The device is unique in that the reagent is generated electronically, which means that no standardization or calibration is required. The accuracy of the device is within ± 10 micrograms or 1%, which corresponds to an even greater accuracy. For water determination in Flunisolide, TForm A, where the samples for the determination are between 35 and 75 mg and contain between 700 and 1500 micrograms of water, the accuracy is within ± 0.03% of the amount of water determined in micrograms.

The microprocessor control is used to distinguish between the titration of water contained in the sample and a possible reaction of the Karl Fischer reagent with other compounds such as aldehydes or ketones. The Aquatest IV device is used in accordance with the regulations contained in the instruction manual published by the Photovolt Corporation in July 1978 and as Paper No. in February 1978. 260 at the Pittsburg Conference on Analytical Chemistry and Applied Specroscopy by K.A. Lindblom. The address of Photovolt Corporation is 1115 Broadway, New York, New York 10010.

s io

15

20th

25th

30th

35

40

45

50

55

60

65

643 567

4th

In the method according to the invention it is important that the device used for the crystallization of flunisolide is completely clean. If a different polymorphic form of flunisolide is present in the flask or container in which the crystallization takes place, the desired form A can be contaminated with another phase which is formed at the same time because the crystallization is influenced by the flunisolide crystals present. It is therefore advisable to thoroughly wash all devices with the alkanol to be used, e.g. aqueous n-butanol, to ensure that any flunisolide present as a foreign substance is completely removed from the devices with another crystal form.

As already explained above, the process according to the invention consists in the crystallization of flunisolide from a solution in an aqueous alkanol with 3 or 4 carbon atoms. The alkanols with 3 or 4 carbon atoms include e.g. Isopropyl alcohol, n-propanol, n-butanol, isobutyl alcohol, sec-butyl alcohol and tert-butyl alcohol, n-butanol is preferred. The alkanol contains water, i.e. it contains approximately 0.2 to 5% by volume, preferably

1 to 4% by volume, water. In the case of n-butanol, approximately 2.3% by volume of water are preferably 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 a crystalline form, followed by stirring or shaking until the flunisolide is completely dissolved. The desired amount of water can then be added. However, an aqueous alkanol can also be used for the preparation of the solution. In order to accelerate the dissolution process, the alkanol can be heated to a temperature of 75 ° C or more up to its boiling point (e.g. for n-butanol 117 ° C). However, the alkanol can also be added to an already existing solution of flunisolide in another solvent with a lower boiling point than the alkanol. E.g. n-butanol can be added to a solution of flunisolide in methylene chloride, after which the methylene chloride is distilled off while the flunisolide is dissolved in the n-butanol. This is done e.g. by displacement distillation. It is of course important to use enough alkanol to keep the flunisolide in solution. Then water is added. The flunisolide concentration therefore depends on the alkanol used. It was found that about 50 g of flunisolide at 80 ° C in 250 ml of n-butanol, the

Contains 2 vol .-% water, dissolve and crystallize from the solution at about 35 ° C, the new crystalline form A is obtained.

Once a solution of flunisolide has been obtained in the alkanol, crystallization of the flunisolide is carried out, preferably at a temperature less than about 75 ° C. This can e.g. by slowly adding an n-buta-nol solution, e.g. at a rate of 1 ° C per 30 seconds to about 10 minutes. The initial temperature of the solution in the aqueous alkanol can be anywhere between about 30 ° C and about the boiling point of the alkanol.

Although the desired form A of flunisolide is obtained if the crystallization is allowed to proceed solely by cooling, such a method may not always be economically advantageous because a large amount of flunisolide remains in solution. When operating on a small scale, a suitable alkane solvent (in which flunisolide is sparingly soluble) can be added to the alkanol solution to displace the flunisolide from the solution. The alkane solvent is preferably n-hexane or n-heptane. Generally about twice to about five times the volume of n-hexane or n-heptane, based on the volume of the alkanol solution, is added, and this amount is added over a longer period, e.g. about 10 minutes to 4 hours or more, depending on the volume of the solvents used, slowly added to the alkanol solution containing about 50 g of flunisolide. E.g. 750 ml of n-hexane can be added to about 250 ml of a solution of flunisolide in aqueous n-butanol in the course of an hour. The alkane solvent may be the same temperature or a lower temperature than the solution in n-butanol, but is preferably at ambient temperature, i.e. approx. 20 to 25 ° C, so that the crystallization proceeds faster.

After the steroid crystals have been obtained,

they are dried in a manner known per se, such as by drying in vacuo, in order to remove all solvent. This can be done within a period of 2 hours to several days.

The unique crystal structure of flunisolide, which is shown in the X-ray diffraction pattern shown in Table A, can be compared to other polymorphic forms of flunisolide by analysis using the Debye-Scherrer diagram, using differential calorimetry with an automatically registering device A distinction can be made between microscopy in polarized light, water analysis and microscopy with a heatable microscope.

The following examples illustrate certain representative conditions which are suitable for the process according to the invention.

example 1

50 g of moist flunisolide (which contains approx. 1% by weight of water) are placed in a 1 liter Erlenmeyer flask equipped with a magnetic stirrer, followed by 250 ml of n-butanol, which contains approx. 0.1% by volume. Contains water to be added. The mixture is heated to 70 ° C until complete dissolution is achieved, after which the solution is allowed to cool slowly at a rate of approximately 1 ° C per minute. Crystallization can be determined at approx. 35 ° C, and n-heptane is slowly added at 30 ° C over a period of approximately one hour until the total volume of the mixture is 1 liter. After stirring for a further 1 hour at ambient temperature, the product is filtered off, washed several times with n-heptane and air-dried. The product is then dried in a vacuum oven at 50 ° C. for 3 days, 45 g of flunisolide being obtained using the Debye-Scherrer diagram shown in Table A.

Analysis of the crystals using Karl Fischer reagent in an Aquatest IV device shows a water content of 1.93%.

Example 2

100 g of flunisolide are placed in a 500 ml Erlenmeyer flask equipped with a magnetic stirrer, whereupon 196 ml of analytically pure n-butanol and 4 ml of distilled water are added. The mixture is heated to 95 ° C with stirring until complete dissolution is achieved and then cooled with stirring. Crystallization is detectable at approx. 70 ° C. The resulting slurry is cooled to room temperature and stirred overnight. The product is then filtered off and air dried to give 85 g of flunisolide using the Debye-Scherrer diagram shown in Table A.

Analysis of the resulting crystals using US5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

of Karl Fischer reagent in an Aquatest IV device gives a water content of 1.93% by weight.

Example 3

10 g of flunisolide are placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer, after which 15 ml of n-propanol and 0.6 ml of distilled water are added. The mixture is heated to 90 ° C. with stirring until complete dissolution is achieved and then cooled with stirring. Crystallization is detectable at about 60 ° C and the resulting slurry is cooled to room temperature with stirring. After stirring overnight at room temperature, the product is filtered off and air-dried to give 8.6 g of flunisolide using the Debye-Scherrer diagram shown in Table A.

Analysis of the crystals using Karl Fischer reagent in an Aquatest IV device shows a water content of 2.08% by weight.

Example 4

10 g of flunisolide are placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer, after which 20 ml of isopropyl alcohol and 1 ml of distilled water are added. This mixture is heated to about 70 ° C until a clear solution is obtained and then cooled with stirring. Crystallization is detectable at 50 to 60 ° C. The resulting slurry is cooled to room temperature and stirred overnight. After standing for 6 days at room temperature, filtering off, drying in air and drying in vacuo at room temperature for 24 hours, 8.5 g of flunisolide are obtained using the Debye-Scherrer diagram shown in Table A.

Analysis of the crystals using Karl Fischer reagent in an Aquatest IV device shows a water content of 2.18%.

Example 5

2 g of flunisolide with the X-ray diffraction pattern shown in Table A are placed in a flask containing 10 ml of 95% room temperature ethanol. The mixture is heated with stirring until all of the flunisolide is completely dissolved. The resulting solution is then allowed to cool to room temperature while scraping the side walls of the flask with a glass rod to initiate crystallization. The crystals obtained are analyzed by polarized light microscopy to find that they are different from the flunisolide initially used.

Example 6

The procedure of Example 5 is repeated, but the crystallization is initiated by using a

643567

inoculate a small amount of flunisolide using the X-ray diffraction pattern shown in Table A. The crystals thus obtained are analyzed by polarized light microscopy, and are found to be different from the flunisolide used as the seed crystals.

Example 7

50 g of flunisolide are added to 600 ml of methanol, which is heated to dissolve all of the flunisolide and then allowed to cool. The volume of the resulting solution is reduced in half on a rotary evaporator, whereupon the resulting slurry is filtered and crystalline flunisolide is isolated. The filtrate is again evaporated to a volume of approximately 60 ml and then filtered as above. The resulting product is air dried to give 26 g of flunisolide, which differs from flunisolide with the X-ray diffraction chart shown in Table A, such as analysis by X-ray diffraction diagrams, differential calorimetry with a registering device, visual thermal analysis and weight loss when heated 2.6% is found.

Example 8

100 mg of flunisolide are dissolved in 20 ml of absolute ethanol at approximately 70 ° C. The resulting solution is cooled to room temperature, after which it is allowed to evaporate within a period of 3 days. The resulting crystalline flunisolide is collected, analyzed by X-ray diffraction, differential calorimetry with a registration device, visual thermal analysis and weight loss on heating (4.5%, 4.9%). The resulting crystalline flunisolide is found to be different from the crystalline flunisolide shown in the X-ray diffraction chart shown in Table A.

Example 9

10 g of flunisolide are placed in a 50 ml Erlenmeyer flask equipped with a magnetic stirrer, after which 20 ml of tert-butyl alcohol and 1 ml of distilled water are added. This mixture is heated until a clear solution is obtained and then cooled with stirring until crystallization is detectable. 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 give flunisolide using the X-ray diffraction pattern shown in Table A.

Analysis of the crystals using Karl Fischer reagent in an Aquatest IV device shows a water content of approx. 2% by weight.

5

5

10th

15

20th

25th

30th

35

40

45

50

B

Claims (7)

643 567 2nd PATENT CLAIMS 1. A process for producing a crystalline form of flunisolide containing 2.0 ± 0.2% by weight of water and having the X-ray diffraction pattern shown in Table A: Table A d i / n 0 Â % Degree 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 10th 7.0 5.98 90 7.4 5.53 100 8.0 5.21 60 8.5 5.06 60 8.8 4.79 10th 9.3 4.55 70 9.8 4.33 1 10.3 4.13 10th 10.8 3.95 10th 11.3 3.86 5b 11.5 3.70 5 12.0 3.63 10th 12.3 3.36 1 13.3 3.30 2nd 13.5 3.21 2nd 13.9 3.03 1 14.8 2.88 2nd 15.5 2.67 2 B 16.8 2.63 1 17.0 2.60 1 17.3 2.56 1 17.5 2.40 3rd 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 2nd 24.3 characterized in that the flunisolide is crystallized from a solution of flunisolide in a liquid alkanol having 3 or 4 carbon atoms and containing 0.2 to 5% by volume of water. 2. The method according to claim 1, characterized in that one uses a solution containing 1 to 4 vol .-% water. 3. The method according to claim 1 or 2, characterized in that n-butanol is used as the alkanol. 4. The method according to claim 1 or 2, characterized in that isopropyl alcohol or n-propyl alcohol is used as the alkanol. 5. The method according to any one of claims 1 to 4, characterized in that the solution in the alkanol is allowed to cool from a temperature above 75 ° C to a temperature below 75 ° C during crystallization. 6. The method according to any one of claims 1 to 5, characterized in that the solution is cooled to a temperature below 30 ° C. 7. Crystalline form of flunisolide, which contains 2.0 + 0.2% by weight of water and which has the X-ray diffraction diagram shown in Table A below: Table A d I / Ii 0 Â % Degree 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 10th 7.0 5.98 90 7.4 5.53 100 8.0 5.21 60 8.5 5.06 60 8.8 4.79 10th 9.3 4.55 70 9.8 4.33 1 10.3 4.13 10th 10.8 3.95 10th 11.3 3.86 5b 11.5 3.70 5 12.0 3.63 10th 12.3 3.36 1 13.3 3.30 2nd 13.5 3.21 2nd 13.9 3.03 1 14.8 2.88 2nd 15.5 2.67 2 B 16.8 2.63 1 17.0 2.60 1 17.3 2.56 1 17.5 2.40 3rd 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 2nd 24.3 obtained by the process according to claim 1. 8. Crystalline form of flunisolide according to claim 7, obtained by the process according to one of claims 2 to 6.