CA1147652A - Beclomethasone ester solvates - Google Patents

Abstract

April 24, 1980 JB/vl ABSTRACT

The present invention relates to novel solvates of beclo-methasone dipropionate with alkanes, especially n-alkanes, having from 5 to 8 carbon atoms, and to their preparation, e.g. by contacting beclomethasone dipropionate with the alkane. The novel solvates can be used in inhalation de-vices and in the preparation of beclomethasone dipropionate-trichlorofluoromethane solvate.

Description

'~ECLOMETHASONE ESTER SOLVATES"

, This invention relates to novel solvates of a beclo-methasone ester, namely beclomethasone dipropionate, to processes for their preparation, and to their use in the preparation of aerosols.
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Beclomethasone dipropionate is ~a-chloro-16~-methyl-1,4--pregnadiene-11~,17a~?1-triol-3,20-dione 17a,21-dipropionate and has the following structural formula:

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I H2--C-CH2CH3, HO ~ H l~2CH3 ' O
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i 10 It is`a useful drug for the treatment Or chronic allergic asthma (Brit.Med.J., 1, 585-590 (1972)) and is typically administered in an aerosol unit containing a microcrystal-line suspension of beclomethasone dipropionate in a .~ ' 31i~

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propellant, usually trichloro~luoromethane. The drug must be micronized prior to use in an aerosol formulation in order to obtain particles of medicinally effective si~e~ However, when unsolvated drug is introduced into the aerosol formu-lation, the micronised drug particles solvate and undergo cry-stal growth, which reduces the amount of drug of suitable ~- particle size available in the spray and also causes the aerosol spray valves to clog. To overcome this problem of crystal growth, it has been found useful to prepare a so1-vate of the drug with the trichlorofluoromethane propellant prior to micronization of the drug (British Patent Specifi-., cation No. 1,429,1~4). The drug solvate is then micronized ;` and mixed with the remaining aerosol propellants. Althou~h the beclomethasone dipropionate-trichlorofluoromethane-~sol-vate thus enables one to prepare a suitable aerosol form, it presents other manufacturing difficulties in that the sol-vate when stored as bulk is not stable with respect to tri-ii~l chlorofluoromethane. Trichlorofluoromethane is released .,, ~ .
when the solvabe is stored at room temperature or above, and thus the solvate must be used rather promptly or be stored ~:, under rePrigeration. Storage under refrigeration is bothexpensive and inconvenient, particularly when the drug sol-vate is to be shipped in bulk. Moreover, a substantial por-tion (up to one third) of the trichlorofluoromethane is lost ,........... .
from the trichlorofluoromethane solvate during the microni-zat;on. The loss of the trichlorofluoromethane from the drug ; ' ' ' -4 ~
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solvate results in a loss of micronized drug in the aerosol formulation since (as mentioned above) any unsolvated drug will tend to undergo crystal growth and thus not be medici-nally available in the aerosol spray. The lost trichloro-fluoromethane is also a potential environmental hazard.

The present invention is based upon the surprising discovery that beclomethasone d;propionate forms solvates with alkanes which are substantially stable with respect to alkane when stored as bulk.

The present invention therefore provides solvakes of beclo-methasone dipropionate with alkanes having from 5 to 8 carbon atoms. For the purposes o~ this invention we de-fine the term "solvate" as a crystalline material in which the steroid beclomethasone dipropionate and the alkane are associated. Mo particular method of associa-tion is implied, but it is possible that the alkane occupies '~ "holes" in the crystal lattice of the steroid. The solvate normally contains from 4 to 8% by weight of alkane, the amount depending upon the particular method of preparation as well as upon the alkane itself. The alkane is preferably an n-alkane, ;.e. n-pentane, n-heptane or n-octane, or especially n-hexane.

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. ., 7~6 The accompanying drawing shows the infrared absorption spectrum o~ a mull of beclomethasone dipropionate-_-hexane solvate in mineral oil (sold under the Trade Mark "Nujol").
In the drawing the vertical scale indicates the transmittance (shown by "T ( % )"), and the horizontal scale indicates the frequency in cm. 1 (shown by " V(cm. 1)~) and the wavelength in microns (shown by " ~ )"). This sample of solvate con tained 4-5% of n-hexane by weight. Beclomethasone dipropio-nate-n-hexane solvate normally contains 4 to 6~ by weight of n-hexane, in particular about 4.6% Dr 5.3% by weight of n-hexane.
`; , ' The infrared spectra of beclomethasone dipropionate-n-pentane solvate and of beclomethasone dipropionate-n-heptane solvate are very similar to the spectrum shown in the accompanying drawing~ in that all these spectra have absorption bands in almost identical positions. The relative intensities of so~e absorption bands may vary, depending upon the n-alkane in the solvate and how much of it is present in the solvate.
A particular solvate may also show a few absorption bands not , 20 characteristic of other solvates.

The beclomethasone dipropionate-alkane solvates are stable with respect to the alkane at moderate temperatures. In par-ticular, beclomethasone dipropionate-n-hexane solvate is ~' ~' ' . , , . - - , .
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i2 stable with respect to n-he~ane at temperatures up to about 100C.~ n-hexane is- first lost at about 105C. (as sh~wn by differential thermal analysis). The n-hexane solvate can however be broken at 80C. under vacuum.
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The solvates according to the invention can be prepared by intimately contacting beclomethasone dipropionate with an alkane having from 5 to 8 carbon atoms. Although it may be ~ convenient under particular circumstances to contact micro-; nised beclomethasDne dipropionate with the alkane, it is generally preferable to allow the beclomethasone dipropionate to crystallise out o~ an organic solvent medium comprising the alkane. Although the organic solvent medium may be pure alkane (e.g. if the beclomethasone dipropionate is extracted out of a Soxhlet), it preferably comprises the al-karle and an organic solvent that is completely misclbletherewith, e.g. chloroform, tetrahydrofuran, dioxan, di-iso-propyl ether, diethyl ether, ethyl acetate, cyclohexane, acetonltrile, isopropanol, or especially methylene chlo-rîde or acetone. The alkane is preferably an n-alkane, i.e.
n-pentane, n-heptane or n-octane or especially n-hexane.
The solvate is conveniently prepared by dissolving the beclo-.
` mekhasone dipropionate in a sui~able organic solvent (such-as one mentioned above) and then adding the alkane; preferab-ly the original solvent is then at least partly removed by di~tillation, while further-alkane is added to malntain total .- . .
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solvent volume. After cooling, the precipitated solvate is filtered off and dried.

The alkane solvates of this invention and in particular the n-hexane solvate of beclomethasone dipropionate are simpler to prepare than the known trichlorofluoromethane so:Lvate, - in that7they can be prepared without using the large volumes of solvating medium that the trichlorofluoromekhane solvate needs.

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, The novel beclomethasone dipropionate-alkane solvates ; 10 are suitable for use in the preparation of beclomethasone - dipropiona~e-trichlorofluoromethane solvate especially of an appropriate particle size (e.g. 1 to 10~) for use as active ingredient of an aerosol formulation. The invention therefore provides a process for the preparation of beclomethasone dipropionate-trichlorofluoromethane solvate whlch comprises bringing a solvate of beclomethasone dipro-ionate with an alkane having 5 to 8 carbon atoms into contact with trichlorofluoromethane. Preferably the alkane solvate r ' iS micronised, so that the resulting trichlorofluoromethane 20 solvate is also micronised. The method of preparation of beclomethasone dipropionate-trichlorofluoromethane solvate according to the present invention furthermore has the ad-vantage of not requiring such large volumes of trichloro-fluoromethane as are required by the known method. For , . , - . . . ....
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example, when the beclomethasone dipropionate-n-hexane solvate is contacted with a relatively small volume of tri-chlorofluoromethane, e.g. 15 litres per kg, of solvated steroid, the n-hexane of solvation is exchanged for trichlorofluoro-methane so that beclomethasone dîpropionate-trichlorofluoro-methane solvate is formed. (Preparation of the trichloro-fluoromethane solvate by the method of British Patent Speci-fication No~ 1,429,184, Example 2, would require about 140 litres of trichlorofluoromethane per kg. of steroid.) - 10 This process is preferably carried out on micronised beclo-methasone di:propionate-n-hexane solvate so that mlcronised beclomethasone dipropionate-trichlorofluoromethane solvate is isolated. Alternatively and preferably, micronized beclomethasone diproplonate-alkane solvate (especially the n-hexane solvate) may be placed directly in the aerosol canîster with the trichlorofluoromethane propellant to afford in situ an aerosol formulation in which the beclo-methasone dipropionate does not exhibit significant crystal growth and exists in a particle size suitable ~or local , .
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Since the beclomethasone dipropionate-trichlorofluoro-methane solvate prepared by this method retains sub-stantially the particle size of the micronized beclo-methasone dipropionate-alkane solvate, it may be used dlrectly without further micronization in an aerosol formulation, so that loss of trichlorofluoromethane and consequent crystal growth`on resolvation can be avoided.

~ The amount of alkane (e.g~ n-hexane) present in the sol-; vate of this invention is considered biologically in-significant and thus the alkane solvate may be used ~- direCtlyin a formulation without toxic effects.

The aerosol propellants and valves suitable ~or use in this feature of the invention are standard and well known in the art. A particularly suitable inhaler is the inhaler presently marketed under the Trade Mark Vanceril.

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~he following examples illustrate but do not limit the present invention:

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: 9 Beclomethasone Dipropionate-n-Hexane Solvate Dissolve 300 g. of beclomethasone dipropionate in 2 liters of methylene chloride at reflux. Treat with 15 g.
activated charcoal for 15 minutes at reflux and filter while hot. Concentrate the filtered solution to a vo-lume of 900 ml. and while maintaining reflux add slowly 900 ml. of n-hexane. Cool to 0-10C. Filter off the resulting precipitate and wash it with n hexane. Dry the precipitate in air below 50C. to constant weight ` to afford beclomethasone dipropionate-n-hexane solvate having an [a]D = ~85.5 ~ 2 in dioxan and an 1%
(extinction coeff;cient) in 1% solution - 275 ~ 10 at 239 m ~ . Analysis by gas chromatography shows an n-hexane content of 4.6%. The beclomethasone dipropionatecontent (determinedby ultrayiolet assay) is 94.5%.

, XAMPLE 2 Beclomethasone Dipropionate-n-Hexane Solvate Dissolve 100 g, of beclomethasone dipropionate in 1.5 liters of acetone at reflux. Treat with 5 g. of acti-vated charcoal for 15 minutes and filter while hot. Con-centrate the filtered solution to 0.5 liter. While j maintaining reflux, slowly add 0.5 liter of n-hexane.

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Cool to 0-10C. Filter o~f the resulting precipitate and wash it with cold n-hexane. Dry the precipitate in air at 50C. to constant weight to yield beclometha-sone dipropionate-n-hexane solvate. The beclomethasone dipropionate content (determined by ultraviolet assay) is 9~.6%~

Beclomethasone Dipropionate-n-Hexane Solvate Under reflux, dissolve 20 g. of beclomethasone dipropionate in 100 ml. of methylene chloride. If necessary~ treat with activated charcoal and-filter. Slowly add 400 ml. of . .
n-hexane while distilling at a rate that maintains a batch volume of 100 ml. Reflux the batch at a volume o~ 100 ml.
~ - (b.p. 68C.) for hal~ an hour. Cool slowly to 0-5C.;
;; 15 filter, wash the precipitate with n-hexane, and dry it at 60C. to constant weight; yield 21 g. n-Hexane by gas chromatography assay (two samples~: 5.29%; 5.07%.

Beclomethasone Dipropionate-n-Hexane Solvate ~ , , .

Under reflux, dissolve 50 g. of beclomethasone dipropionate in 250 ml. of acetone. If necessary, treat with activated charcoal and filter. Distil at a slow rate adding .,,,~, ' , .. . . : , . :

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-.,':, ~ ` ` ` ` ' ` ' ~7~iS;2 n-hexane just fast enough to maintain the original batch ; volume. Continue the distillation until 1 liter of n-hexane has been added and the batch has a volume o~
250 ml. and a boiling point of 68C. Reflux the batch for half an hour and cool it slowly to 0-5C. Filter off the precipitate, wash it with n-hexane, and dry it in the air at 60C. to constant weightj yield 52.8 g.
n-Hexane by gas chromatography assay (three samples):
5.34%, 5.33%; 5.78%.

Beclomethasone Dipropionate-n-Pentane So:Lvate .~
`~ Under reflux, dissolve 2 g. of beclomethasone dipropionate .
in 15 ml, of methylene chloride. Add 10 ml~ of n-pentane and concentrate to 15 ml. Continue the addition/concentra-tion sequence until 150 ml. of pentane has been added and : ::
the batch has a volume of 15 ml. and a boiling point of 36C, Cool slowly to 0 5C. Filter o~f the precipitate, .~ :
wash it with n-pentane, and dry it at 60C. in air to constant weightj yield 1.99 g., ~a~26 (dioxan) +88.9, ; 2~ 1% in MeOH - 285 at 238 m~ . n-Pentane by gas chroma--. .
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, ` tography assay: li 39%

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- Beclomethasone Dipropionate-n-Heptane Solvate - Under reflux dissolve 2 g. of beclomethasone dipropionate in 25 ml. of methylene chloride. Add 7 ml. of n-heptane and bring to reflux under partial vacuum. Slowly add ~; 140 ml. of n-heptane while distilling under reduced pres~
sure so as to maintain a volume of 25 ml. Stir for half .r `~" an hour at room temperature. Cool to 0-5C., f:ilter off the precipitate, wash it with n-heptane and dry it in air at 60C. to constant weight, yield 2.1 g.~ [alD
(dioxan) = ~85.5, ~1% in MeOH - 277 at 238 m~ .
n-Heptane by gas chromatography assay: 7,32%.

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Beclomethasone Dipropionate Inhaler ~ormulamg/container (200 doses) Beclomethasone Dipropionate*(mi cronized~ lO.Q
Oleic Acid 1.0 ;~ Trichlorofluoromethane4,739.0 Dichlorodifluoromethane12,250.0 to make 17,000.0 *Charged as beclomethasone dipropionate-n-hexane solvate ~, 10 equivalent to 10 mg. of beclomethasone dipropionate.

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Procedure Add oleic acid to previously cooled trichlorofluoromethane and mix with a high-`sheer mixer, While mixing~ add khe required amount of beclomethasone dipropionate-n-hexane solvate and continue mixing until homogeneous. If necessary, adjust the suspension to the required weight ` with trichlorofluoromethane. Meter the required amount of suspension into each can. Crimp the valves onto the cans. Pressure-fill through the valves the required ` 20 amount of dichlorodifluoromethane.

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Claims (28)

- 14 - 2122 Canada The Embodiments of the Invention in which an exclusive Pro-perty or Privilege is claimed are defined as follows:

1. A process for the preparation of a solvate of beclo-methasone dipropionate with an alkane having from 5 to 8 carbon atoms, which comprises intimately contacting beclometha-sone dipropionate with an alkane having from 5 to 8 carbon atoms.

2. A process as claimed in claim 1 wherein the alkane is an n-alkane

3. A process as claimed in claim 2 which comprises allowing beclomethasone dipropionate to crystallise out of an organic solvent medium comprising an alkane having from 5 to 8 carbon atoms.

4. A process as claimed in claim 3 wherein the organic solvent medium comprises the alkane and an organic solvent that is completely miscible with the alkane.

5. A process as claimed in claim 4 wherein the organic solvent is chloroform, tetrahydrofuran, dioxan, di-isopropyl ether, diethyl ether, ethyl acetate, cyclohexane, acetonitrile, isopropanol, methylene chloride or acetone.

6. A process as claimed in claim 4 wherein the organic solvent is methylene chloride or acetone.

7. A process as claimed in claim 4 wherein the alkane is n-pentane or n-heptane.

8. A process as claimed in claim 5 wherein the alkane is n-pentane or n-heptane.

9. A process as claimed in claim 4 wherein the alkane is n-hexane.

10. A process as claimed in claim 5 wherein the alkane is n-hexane.

11. Solvates of beclomethasone dipropionate with alkanes having from 5 to 8 carbon atoms, whenever prepared or pro-duced by a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

12. Solvates of beclomethasone dipropionate with n-alkanes having from 5 to 8 carbon atoms, whenever prepared or pro-duced by a process as claimed in any of claims 3 to 5 or by an obvious chemical equivalent thereof.

13. Solvates of beclomethasone dipropionate with n-pen-tane or n-heptane, whenever prepared or produced by a pro-cess as claimed in claim 7 or claim 8 or by an obvious chemical equivalent thereof.

14. Beclomethasone dipropionate-n-hexane solvate when-ever prepared or produced by a process as claimed in claim 10 or by an obvious chemical equivalent thereof.

15. Solates of beclomethasone dipropionate with alkanes having from 5 to 8 carbon atoms and containing from 4 to 8%
by weight of alkane, whenever prepared or produced by a process as claimed in claim 1 or claim 2 or by an obvious chemical equivalent thereof.

16. Beclomethasone dipropionate-n-hexane solvate contai-ning from 4 to 6% by weight of n-hexane, whenever prepared or produced by a process as claimed in claim 10 or by an obvious chemical equivalent thereof.

17. Beclomethasone dipropionate-n-hexane solvate con-taining about 4.6% by weight of n-hexane, whenever prepared or produced by a process as claimed in claim 9 or claim 10 or by an obvious chemical equivalent thereof.

18. Beclomethasone dipropionate-n-hexane solvate contai-ning about 5.3% by weight of n-hexane, whenever prepared or produced by a process as claimed in claim 9 or claim 10 or by an obvious chemical equivalent thereof.

19. Solvates of beclomethasone dipropionate with n-alkanes having from 5 to 8 carbon atoms, whenever prepared or pro-duced by a process as claimed in claim 2 or by an obvious chemical equivalent thereof.

20. Solvates of beclomethasone dipropionate with n-alkanes having from 5 to 8 carbon atoms, whenever prepared or pro-duced by a process as claimed in claim 6 or by an obvious chemical equivalent thereof.

21. A process for the preparation of beclomethasone dipro-pionate trichlorofluoromethane solvate which comprises bringing a solvate of beclomethasone dipropionate with an alkane having 5 to 8 carbon atoms as claimed in any of claim 11, 19 and 20 into contact with trichlorofluoromethane.

22. A process for the preparation of micronised beclo-methasone dipropionte-trichlorofluoromethane solvate which comprises bringing a micronised solvate of beclomethasone dipropionate with an alkane having 5 to 8 carbon atoms as claimed in any of claims 11, 19, and 20 into contact with trichlorofluoromethane.

23. A process for the preparation of beclomethasone dipro-pionate-trichlorofluoromethane solvate which comprises bringing beclomethasone dipropionate-n-hexane solvate as claimed in claim 14 into contact with trichlorofluoromethane.

24. A process for the preparation of micronised beclo-methasone dipropionate-trichlorofluoromethane solvate which comprises bringing micronised beclomethasone dipropionate-n--hexane solvate as claimed in claim 16 into contact with trichlorofluoromethane.

25. A process as claimed in claim 23 wherein the beclometha-sone dipropionate-trichlorofuoromethane solvate is formed in situ in an aerosol formulation.

26. A method of preparing an aerosol formulation of beclo-methasone dipropionate which comprises the step of micronising a solvate as claimed in claim 11 and placing said micronised solvate in an aerosol propellant.

27. A method as claimed in claim 26 wherein the aerosol propellant comprises trichlorofluoromethane.

28. A method as claimed in claim 27 wherein the solvate is beclomethasone dipropionate-n-hexane solvate as claimed in claim 10.