(116e) Continuous mixing of pharmaceutical powder mixtures

Despite of the constraints linked to the traditions of pharmaceutical production, the interest for continuous processes in such industry is now increasing so that we can expect that their use will certainly be current within a decade. In particular, the powder mixing operations that are practically always driven in batch, provoking tedious problems in mixture sampling for homogeneity assessment, will certainly be operated in continuous mode in a near future, as far as other constraints do allow it. However, the inclusion of a continuous powder mixer inside an industrial production line cannot be made in routine, as it requires performing previous pilot-scale, if not full industrial scale, tests. Once given a method for analysing the homogeneity of the mixtures, that may be on-line, the role of theses tests will be to determine the best operating conditions leading to a commercial product. In particular, the discharge of the mixer as well as its feeding mode (either volumetric or gravimetric), are key issues to control. Finding out the capabilities of a given mixer is therefore a risky procedure, as nobody can guarantee in advance that it will be able to give a mixture responding to end-used properties. More of that, one has also to pay attention to the environment of the process itself and in particular to the existence of perturbation that may change the dosage mode, and in turn affect the quality of the mixtures.

In this paper, we report experimental results of continuous mixing obtained in a GCM 500 Gericke mixer operating with three loss-in-weight feeders. A commercial pharmaceutical mixture containing three active components (representing 10%, 4% and 0.5% of the whole mixture) out of nine ingredients, is tested with the aim of changing the actual batch mixing process by a fully continuous process to be adapted just before conditioning. A large set of experimental variables is explored, such as the initial premix configuration of the additives, the stirrer type (blade supported by frame or by the axis of rotation), the rotational speed of the stirrer. Three pharmaceutical standards linked with mixture quality (coefficient of variation, value of the mean, individual values) are calculated at the outlet of the mixer by sampling of twelve consecutive samples of unit size in a conveyor belt. The best conditions with regard to mixture homogeneity standards are determined for each active ingredient. These are then used for studying the stability of the mixture’s quality under "real" industrial conditions: filling of feeders, accidental perturbations, beginning and end of operation. All these perturbations demonstrated to have a direct influence on the quality of the mixtures, therefore providing industrial guidelines that may be of general value.