Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2003-08-19
Aulakh, Charanjit S (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S101000, C544S099000, C544S291000, C514S229500, C514S230500, C546S089000
Reexamination Certificate
active
06608055
ABSTRACT:
The invention relates to a crystalline (1&agr;,2&bgr;,4&bgr;,5&agr;,7&bgr;)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0
2,4
]nonane-bromide in anhydrous form, processes for preparing it and its use for preparing a pharmaceutical composition, particularly for preparing a pharmaceutical composition with an anticholinergic activity.
BACKGROUND OF THE INVENTION
The compound (1&agr;,2&bgr;,4&bgr;,5&agr;,7&bgr;)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0
2,4
]nonane-bromide, is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679BR). Tiotropium bromide is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) and administered by suitable powder inhalers may be used. Alternatively, it may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.
The correct manufacture of the abovementioned compositions which are suitable for use for the administration of a pharmaceutically active substance by inhalation is based on various parameters which are connected with the nature of the active substance itself. In pharmaceutical compositions which are used like tiotropium bromide in the form of inhalable powders or inhalable aerosols, the crystalline active substance is used in ground (micronised) form for preparing the formulation. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well. It is particularly desirable that the active substance should be prepared in the form of a uniform and clearly defined crystalline modification. It is also particularly desirable that the active substance be prepared in a crystalline form which does not tend to form polymorphs.
Apart from the requirements indicated above, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which is capable of improving its physical and chemical stability gives a significant advantage over less stable forms of the same medicament.
The aim of the invention is thus to provide a new, stable crystalline form of the compound tiotropium bromide which meets the stringent requirements imposed on pharmaceutically active substances as mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that, depending on the choice of conditions which can be used when purifying the crude product obtained after industrial manufacture, tiotropium bromide occurs in various crystalline modifications.
It has been found that these different modifications can be deliberately produced by selecting the solvents used for the crystallisation as well as by a suitable choice of the process conditions used in the crystallisation process.
Surprisingly, it has been found that, starting from the monohydrate of tiotropium bromide, which can be obtained in crystalline form by choosing specific reaction conditions, it is possible to obtain an anhydrous crystalline modification of tiotropium bromide which meets the stringent requirements mentioned above and thus solves the problem on which the present invention is based. Accordingly the present invention relates to this crystalline anhydrous tiotropium bromide. Any reference to tiotropium bromide anhydrate within the scope of the present invention is to be regarded as a reference to the crystalline tiotropium bromide according to the invention in anhydrous form.
According to another aspect, the present invention relates to a process for preparing the crystalline form of anhydrous tiotropium bromide. This preparation process is characterised in that tiotropium bromide, which has been obtained for example by the method disclosed in EP 418 716 A1, is taken up in water, the mixture obtained is heated and finally the hydrate of tiotropium bromide is crystallised while cooling slowly. Anhydrous crystalline tiotropium bromide can then be obtained from the resulting crystalline tiotropium bromide monohydrate by drying.
The present invention further relates to crystalline anhydrous tiotropium bromide which may be obtained by the above method.
One aspect of the present invention relates to a process for preparing crystalline anhydrous tiotropium bromide starting from crystalline tiotropium bromide monohydrate which is described in more detail hereinafter.
In order to prepare the crystalline monohydrate, tiotropium bromide, which has been obtained for example according to the method disclosed in EP 418 716 A1, has to be taken up in water and heated, then purified with activated charcoal and, after removal of the activated charcoal, the tiotropium bromide monohydrate has to be crystallised out slowly while cooling gently. The anhydrous form is obtained from these crystals by careful heating to more than 50° C., preferably 60-100° C., more particularly to 70-100° C. under reduced pressure, preferably under a high vacuum, over a period of from 15 minutes to 24 hours, preferably 20 minutes to 12 hours.
The method described below is preferably used according to the invention. In a suitably dimensioned reaction vessel the solvent is mixed with tiotropium bromide, which has been obtained for example according to the method disclosed in EP 418 716 A1. 0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are used as solvent per mole of tiotropium bromide used. The mixture obtained is heated with stirring, preferably to more than 50° C., most preferably to more than 60° C. The maximum temperature which can be selected will be determined by the boiling point of the solvent used, i.e. water. Preferably the mixture is heated to a range from 80-90° C. Activated charcoal, dry or moistened with water, is added to this solution. 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g of activated charcoal are put in per mole of tiotropium bromide used. If desired, the activated charcoal is suspended in water before being added to the solution containing the tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, most preferably about 135 g water are used to suspend the activated charcoal, per mole of tiotropium bromide used. If the activated charcoal is suspended in water prior to being added to the solution containing the tiotropium bromide, it is advisable to rinse with the same amount of water.
After the activated charcoal has been added, stirring is continued at constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, most preferably about 15 minutes, and the mixture obtained is filtered to remove the activated charcoal. The filter is then rinsed with water. 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water are used for this, per mole of tiotropium bromide used.
The filtrate is then slowly cooled, preferably to a temperature of 20-25° C. The cooling is preferably carried out at a cooling rate of 1 to 10° C. per 10 to 30 minutes, preferably 2 to 8° C. per 10 to 30 minutes, more preferably 3 to 5° C. per 10 to 20 minutes, most preferably 3 to 5° C. roughly per 20 minutes. If desired, the cooling to 20 to 25° C. may be followed by further cooling to below 20° C., most preferably to 10 to 15° C.
Once the filtrate has cooled, it is stirred for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, most preferably about one hour, to complete the crystallisation.
The crystals formed are finally isolated by filtering or suction
Sieger Peter
Werthmann Ulrike
Aulakh Charanjit S
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Robert P.
Stempel Alan R.
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