Solid material comminution or disintegration – Processes – With heating or cooling of material
Reexamination Certificate
1999-11-15
2001-11-20
Rosenbaum, Mark (Department: 3725)
Solid material comminution or disintegration
Processes
With heating or cooling of material
C241S065000, C241S260100
Reexamination Certificate
active
06318650
ABSTRACT:
The present invention relates to a process for the continuous production of small-particle preparations of bioactive substances, in which the bioactive substances are homogeneously dispersed in a matrix of thermoplastic auxiliaries, in an extruder divided into a plurality of zones. The invention furthermore relates to an arrangement for the continuous production of corresponding preparations.
The production of powders which contain active substances or other small-particle forms by conventional processes is often very costly and thus of no economic interest because of the number of steps in the processes and the problems of dust at the interfaces between the various steps in the processes.
DE-C 33 32 629 discloses a process for the production of a powder of polymers, where the polymers are melted in a twin-screw extruder, cooled, precrushed and finely ground. This process relates in particular to the powdering of polyethylene.
It is generally known to produce preparations containing active substances by the melt extrusion process.
EP-A 686 392 describes the production of pharmaceutical preparations by extrusion of mixtures containing active substances, with the extrudate subsequently being cold-cut and comminuted to granules.
DE-A 195 22 899 discloses a process for the continuous sintering of pharmaceutical granules, in which the mixture of components is initially partially sintered in the extruder and then conveyed toward the open face of the extruder. The resulting granules are then screened if necessary. However, this process requires the use in every case of lipoid components and does not describe the specific production of comminuted formulations.
The problem with processes of this type is that, on cooling the melts, on the one hand inhomogeneity may occur because the physical properties often differ widely, but on the other hand when oligomeric or polymeric substances are used there may also be a reduction in molecular weight. The homogeneity of the product is often unsatisfactory too.
It is an object of the present invention to find a process for the continuous production of particulate preparations of bioactive substances which results in stable homogeneous preparations, irrespective of the composition, in a straightforward manner.
We have found that this object is achieved by a process for the production of small-particle preparations of bioactive substances, in which the bioactive substance is homogeneously dispersed in a matrix of thermoplastic auxiliaries, in a screw extruder divided into a plurality of zones, wherein there is firstly partial sintering or melting of the matrix auxiliaries and mixing of the bioactive substances with the matrix auxiliaries in a heatable zone, after which the mixture is cooled, precomminuted and finely ground in a cooling zone, the screw geometry in the cooling zone being selected so that the cooling zone has a conveying zone as first zone, followed by a mixing zone and/or a kneading zone.
We have furthermore found an arrangement for carrying out the process according to the invention, which consists of a mixing and cooling unit and of a collecting unit, where the mixing and cooling unit and the collecting unit are connected together to form a system which is closed to the outside, and the mixing and cooling unit consists of an extruder which has heatable and coolable zones and whose discharge opening feeds into the collecting unit which consists of a cylindrical container provided with a conical discharge cylinder.
The process is carried out according to the invention in a screw extruder. The extruder may be a single-screw or multiple-screw extruder, preferably a twin-screw extruder, which is particularly preferably corotating and closely intermeshing.
The screw geometry in the heating zone of the extruder, in which the mixing and the melting or initial sintering take place, can be chosen to be closely intermeshing, intermeshing or non-intermeshing, with closely intermeshing screw geometry being preferred. The screws may rotate in opposite directions or, preferably, in the same direction. In the mixing and melting region, besides conveying elements there are preferably mixing and kneading elements arranged on the screws. Conveying elements are single- and multi-flight screw elements which differ in pitch. Mixing elements are gear-like toothed disk elements or backward-conveying elements provided with perforations, it being possible for some of the perforations to extend as far as the screw root or take up at least half of the helical radius.
Kneading elements are bicuspid or tricuspid disks, with the elements always having a plurality of disks which differ in width and have a differing angle of offset to one another.
The temperature in the mixing and melting zone may be, depending on the mixtures to be processed, in the range from 18 to 300, preferably 30 to 2000° C.
The cooling zone which follows the heating zone essentially consists initially of a conveying zone which is followed by a mixing zone and/or a kneading zone.
It is crucial for success of the process that pure conveying elements are employed in the first part of the cooling zone, in order to minimize the energy input and reduce the shear stress and to maximize the rate of cooling of the melt below the softening point. The conveying region of the cooling zone can be followed directly by a kneading zone to comminute the composition but preferably, in the direction of flow, initially by a mixing zone with mixing elements and then by a kneading zone to comminute the composition.
The jacket of the cooling zone is cooled with a liquid coolant. The temperature in the conveying zone of the cooling zone is preferably adjusted to 5 to 30° C. below the softening point of the composition to be cooled. It is possible for the temperature to be reduced over the entire cooling zone in the direction of flow by up to 150° C. below the softening point, depending on the softening point of the compositions. It may also be advisable for shock cooling to take place in the mixing region of the cooling zone and to cool the jacket to temperatures in the range from −10° C. to +10° C.
To avoid large temperature gradients over the flight cross-section, mixing elements are preferably employed, for example elements conveying in opposite directions and having wide perforations which effect rearrangement of the composition, particularly preferably after one third of the length of the cooling zone. After the temperature of the composition has fallen below the softening point, the solidified composition is comminuted and ground to particulate preparations in the last third of the cooling zone by using bicuspid or tricuspid disks, which may be interrupted by conveying elements.
It is also possible where appropriate to incorporate short conveying elements between the mixing zone and kneading zone, just as it may be advisable to provide short conveying sections between the mixing elements or the kneading elements.
The detailed screw geometry also depends on the sequence of addition of the components and, in specific cases, on the type of aids used.
In the case where a premix of matrix materials, additives and bioactive substances is introduced into the extruder, the screw geometry of the mixing and melting zone (heating zone) is preferably chosen so that initially conveying elements convey the mixture onward, then the mixture is melted in a region in which there are mainly kneading elements, with or without return conveying elements, after which, in the following cooling zone, there are initially a conveying zone, a mixing zone and a comminuting zone.
In another possible design of the process, initially matrix auxiliaries and other additives are metered into the extruder, conveyed in the direction of flow by means of conveying elements, and melted in a region in which mixing elements predominate. Then a mixture of bioactive substance and, where appropriate, a release agent is metered in and homogenized with the melt in another mixing region. The temperature in the homogenizing region can be higher
Breitenbach Jorg
Zettler Hans Dieter
BASF - Aktiengesellschaft
Keil & Weinkauf
Rosenbaum Mark
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