Oxidation inhibitors in prostane derivatives

Details Oxidation inhibitors in prostane derivatives Oxidation inhibitors in prostane derivatives

2001-03-07

2003-01-28

Barts, Samuel (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C560S121000, C546S322000, C514S573000

Reexamination Certificate

active

06512139

ABSTRACT:

The invention relates to the use of an oxidation inhibitor for the ambient air in industrial manufacturing, especially in the processing of prostane derivatives, in this case preferably during the wet phase.
PRIOR ART
The active ingredient “iloprost-&bgr;-cyclodextrin” bears the systematic designation 5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]-octen-3-ylidene pentanoic acid as a &bgr;-cyclodextrin inclusion compound. The active ingredient is manufactured in the form of crude pellets by the following steps.
(i) Mixing of the active ingredient iloprost-&bgr;-cyclodextrin and the adjuvants lactose and avicel,
(ii) Pelletization with about 20.5% water,
high-speed mixing,
extruding and
spheronization,
(iii) Drying in a fluidized-bed dryer,
filling and
drying.
The individual steps are described in detail in the following literature: H. SUCKER, P. FUCHS, and P. SPEISER: Pharmazeutische Technologie [Pharmaceutical Technology], Georg Thieme Verlag, Stuttgart, N.Y., 2nd Edition, 1991.
It should be noted that the pelletization in step (ii) is carried out intermittently, i.e., the active-ingredient-containing powder mixture with 0.1% iloprost is processed in cycles in about 5 kg portions. The moist crude pellet cycles are first collected in succession in a fluidized-bed dryer. After the last cycle in the dryer takes place, the final drying begins.
In the above-mentioned production process, methane-diol-ketone contamination occasionally occurred in addition to the pure iloprost. This corresponds to the nomenclature with the name (1S,2R,3R,5R)-3-hydroxy-2-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl-bicyclo[3.3.0]octan-7-one. In this case, this is a decomposition product that is produced by oxidation. In the case of an occurrence, various parameters were important for the amount of decomposition product. In the wet state, the oxidation depended on the water content and the incubation time. It was seen that the temperature can play a role. It was also obvious that the active ingredient was sensitive to the mixture with avicel and lactose, but not to the active ingredient by itself. Although the same parameters were maintained, different amounts of decomposition product, which occasionally was allowed below the detection limit of <0.1%, were produced. Thus, occasionally values of between 0.6% to 4% were used. As a result, the purity requirements were not always met.
OBJECT AND ACHIEVEMENT
The object is thus to offer oxidation protection in the production, especially in the processing of prostane derivatives, whereby the oxidation products are avoided or are considerably reduced in their concentration.
The object is achieved by using an oxidation inhibitor for the ambient air in the case of industrial manufacturing, especially in the processing of prostane derivatives, whereby the oxidation inhibitor removes ozone from the process air before making contact with the prostane derivatives.
Oxidation Inhibitors
The oxidation inhibitor can be
an inert gas atmosphere,
a closed circuit that consists of synthetic air,
a metal catalyst,
an irradiation device with ultraviolet light,
a heating: device with temperatures of at least 250° C. and a cooling device of the process air, or
an activated-carbon filter, through which the process air flows.
Combinations that consist of oxidation inhibitors are also possible.
The oxidation inhibitors are characterized as follows:
An inert gas atmosphere can consist of a nitrogen atmosphere or else a noble gas.
Synthetic air is run as a circuit, whereby the water that accumulates during drying must be removed. In this case, the composition of the process air can essentially correspond to the atmospheric air with the exception of ozone.
Platinum, copper or magnesium oxide may be metal catalysts.
Irradiation with ultraviolet light is preferably carried out at 254 nm.
The process air is heated preferably to 300° C. in the heating device. In this case, this air must then again be cooled in the cooling device. Both processes are preferably carried out in a heat exchanger.
Advantages
The different amounts of decomposition product with otherwise identical parameters were randomly determined as a function of the ozone content in the outside air. In this case, it can be noted that a monitoring of the ozone concentration in the pharmaceutical range is uncommon. Such monitoring has still not been described. A complicating factor is the fact that the decomposition products only occur if a threshold value of about 20 &mgr;g of ozone/m
3
of ambient air is exceeded in the production. Consequently, no clear connection between the ozone concentration and the outside air was to be seen, so that a technical solution, which can suppress the decomposition products satisfactorily, was unlikely.
State of the Prostane Derivatives
Use of an oxidation inhibitor is preferred, whereby the prostane derivatives are mixed with cyclodextrin.
It has been shown that the oxidation occurs to an increased extent if the prostane derivatives are mixed with cyclodextrin. It is known, however, that specifically the complexes that consist of prostane derivatives and cyclodextrin are especially stable relative to an oxidation. Here, an otherwise common principle is thus violated.
The use of an oxidation inhibitor is preferred, whereby the prostane derivatives are found in a wet phase.
The presence of water results in an increased oxidation. Specifically in this case, oxidation proceeds more vigorously. As a result, the handling of the entire process is made more difficult, however. The moisture in the prostane derivatives and preferably in the complexes that consist of prostane derivatives and cyclodextrin must be removed. In this respect, cold traps or other devices are necessary to remove the water vapor from the process air.
Preferred is an activated-carbon filter with the following properties: (i) short contact times, (ii) minimum possible pressure drop through the filter, (iii) activated carbon has hydrophobic properties, and (iv) the filters have long service lives.
Prostane Derivatives
Preferred are prostane derivatives of general formula I or formula II
in which
X
1
is a —CH
2
—CH
2
—; trans —CH═CH— or —C≡C—,
X
2
is a straight-chain or branched, saturated alkylene group with 1 to 6 carbon atoms,
X
3
is an —O— or —CH
2
—,
X
4
is a —CH
2
— or —[CH
2
]
3
—,
X
5
is an —H or —C≡C—R
2
,
R
1
is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 or 6 carbon atoms or phenyl group,
R
2
is a straight-chain or branched-chain, saturated or unsaturated alkyl group with 1 to 6 carbon atoms,
R
3
is a hydrogen atom, an acyl radical with 1 to 4 carbon atoms or a benzoyl radical, and
R
4
is an —H or —CH
3
;
whereby the —O—R
3
group is in &agr;- or &bgr;-position, and their salts with physiologically compatible bases, if R
1
has the meaning of a hydrogen atom.
X
2
stands for straight-chain or branched, saturated alkylene groups with 1 to 6 carbon atoms, thus, for example, methylene, ethylene, propylene, isopropylene, whereby the methyl group is connected to the first or second carbon atom of ethylene, calculated from group A; butylene, methylpropylene, ethylethylene, dimethylethylene, whereby the methyl or ethyl group is connected arbitrarily to the alkylene chain; pentyl, methylbutylene, dimethylpropylene, ethylpropylene, methylethylethylene, whereby the methyl or ethyl groups are connected arbitrarily to the alkylene chain; hexylene, methylpentylene, dimethylbutylene, methylethylpropylene, whereby the methyl or ethyl group is connected arbitrarily to the alkylene chain.
Alkyl group R
1
comprises straight or branched alkyl groups with 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or hexyl.
Cycloalkyl group R
1
can contain 5 or 6 carbon atoms in the ring.
Alkyl group R
2
can consist of straight-chain or branched-chain, saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms

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