United States Patent:  6,054,145

Assignee:  Akzo Nobel, N.V. (Arnhem, NL)

Filed:  March 12, 1999

Disclosed is a process for the preparation of pharmaceutical dosage units containing as an active substance of from 0.005 to 1.0% by weight of micronised Org 30659, comprising (a) a mixing step comprising bringing into association the active substance and a suitable carrier to form a mixture, and (b) a granulating step in which the mixture is granulated to form agglomerates or granules by wetting the mixture with a binder liquid, the wetting being conducted under agitation, characterised in that the granulation step (b) is conducted so as to exert on the granules a shear force which does not exceed the tensile strength of the agglomerates or granules. The process leads to granules and tablets having an excellent content/uniformity.

SUMMARY OF THE INVENTION

To this end, the invention provides a process of the aforementioned type, wherein the granulation step (b) is conducted so as to exert on the granules a shear force which does not exceed the tensile strength of the agglonerates or granules. Without detracting from the further description of the invention given below, this can be achieved, in a typical embodiment of the invention, by avoiding the regular high shear when conducting the granulation. This is a departure from what is generally done in the art, where advanced high shear mixers form a standard device to make granules that can be used for filling capsules or for being processed into tablets.

In the art of making pharmaceutical dosage units by (wet) granulation, high shear mixers have become a conventionally used apparatus in which mixing and granulating is conducted. This type of equipment has considerable advantages, notably as it leads to the optimal mixing of the constituents of a pharmaceutical formulation. Furthermore, the process is well-contained and the available modern equipment enables full in-process control. Surprisingly, in the case of micronised steroids such as Org 30659 present in a low amount, the granulation process leads to a better content uniformity if the actual granulation step, i.e. wetting with binder liquid, while applying agitation, is conducted with substantially lower shear than normally applied in the current high-shear mixers.

In accordance with the invention, it has been recognised that the initial granule strength is the critical parameter for obtaining good content uniformity. This is a surprising finding, as the person skilled in the art will normally apply as high agitation forces as possible, since this leads to a uniform mixture having a good particle size distribution, as the always occurring lumps of material are broken down. However, in the case of low dose Org 30659, it was found that when the process of WO 96/09056 is conducted in a high shear mixer in a normal fashion, the content uniformity cannot be steered to an RSD of below 3% and the DP typically is 30-40%. When following the process of the invention, an excellent DP of well below 10% and consequently favourable content uniformity is obtained.

Without wishing to be bound by theory, the applicant believes that from the results obtained with the present invention, the following mechanism for the demixing occurring under high shear can be deducted. After the addition of binder liquid to the mixture formed under (a), locally overwetted regions will exist. These regions of the mass will give rise to the majority of the largest granules. These initially formed lumps cannot withstand the forces exerted thereon by a high shear mixer. This leads to a constant destruction of agglomerates in which a constant rearrangement of primary particles will unavoidably take place. The state of densification and saturation in which agglomerates can survive, is reached at first for agglomerates containing small primary particles, and these are subsequently able to grow. As a result, the biggest granule particles consist of the smallest primary particles. When drug particles are relatively small as compared to the excipient particles, as is the case with micronised steroids, the coarse granules contain the highest concentrations of the active substance. In accordance with the invention, this destructive nucleation growth mechanism is circumvented, since by lowering the impact pressure of the impellor of a high shear mixer, the above demixing phenomena are avoided.

It is preferred according to the invention if the first step, i.e. mixing the ingredients, is conducted in a normal fashion, i.e. in a conventional high shear mixer applying the regular shear forces. Of course, the subsequent granulation step can be conducted in a different apparatus applying lower shear, it is preferred to use the same apparatus as with mixing, but to make it run at a lower speed and/or with different equipment, so as to have the required lower shear.

Claim 1 of 7 Claims

1. A process for the preparation of pharmaceutical dosage units containing as an active substance of from 0.005 to 1.0% by weight of micronised Org 30659, comprising (a) a mixing step comprising bringing into association the active substance and a suitable filler to form a mixture, and (b) a granulating step in which the mixture is granulated to form agglomerates or granules by wetting the mixture with a binder liquid, the wetting being conducted under agitation, wherein the granulation step (b) is conducted so as to exert on the granules a shear force which does not exceed the tensile strength of the aggolomerates or granules.

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