Comportement du stéarate de magnésium lors du mélange de poudres pharmaceutiques

This research project was performed as a partnership between the Unité de Recherche en Procédés d'Écoulements Industriels (URPEI) of the Chemical Engineering Department of the École Polytechnique de Montréal and ratiopharm opérations. It is well documented in the litterature that magnesium stearate (MgSt), a widely used lubricant in tablet formulation, has a deleterious effect on the physical properties of the tablets if it is used in excessive amounts. Since nearly all formulations require a minimal amount of MgSt in order to be compressible, there exists for each of them an optimal amount of MgSt to add, high enough so that acceptable tablets can be produced at an industrial rate and low enough so that the tablets' physical properties are nearly identical to those of tablets produced from unlubricated excipients.

The main objective of this research project is to gain further insight in the mixing process of MgSt and its influence on the compression behaviour of lubricated excipients. This objective was reached in two steps, the first being to ensure that the MgSt was homogeneously mixed to a model formulation of microcrystalline cellulose (MCC) and spray-dried lactose and the second being to study the link between the amount of MgSt added and the tablets' physical properties.

The mixing of MgSt to the other excipients was studied through mixing experiments involving a V-blender. The MgSt was first made radioactive in the SLOW-POKE nuclear reactor of École Polytechnique de Montréal and samples were extracted from the powder bed with a core sampler. The evolution of the mixing process was studied through the detection of the gamma-rays emitted by the MgSt in each sample and the construction of mixing curves based on the relative standard deviation (RSD). 4 mixing parameters were studied: the loading profile (left-right or top-bottom), the rotational speed (26 or 41 rpm), the loading volume (30, 50 or 70%) and the amount of MCC present (50 or 100%). Results indicated that the mixing performance is very dependent on the loading volume, the rotational speed as well as the amount of MCC, but is not significantly influenced by the loading profile, the latter conclusion being quite unexpected.

Once the optimal mixing conditions were known, three blends, each produced at a 70% loading volume, a 26-rpm rotational speed and a left-right loading profile and lubricated with 0.25, 0.5 and 0.75% MgSt respectively, were compressed into tablets with a lab-scale press. The tablet mass was set at approximately 100 mg. The mass, hardness, thickness, friability and disintegration time of the tablets were measured and compared to those of tablets produced from unlubricated excipients. It was possible to obtain acceptable tablets for very long compression runs for each amount of MgSt, which was not the case in the absence of MgSt. The physical properties measured indicated that an amount of MgSt as low as 0.25% allowed the production of tablets similar to those obtained from unlubricated excipients; however, the tablet hardness diminished significantly when the amount of MgSt reached 0.75% and this led to an improvement in disintegration time over tablets made exclusively of MCC and spray-dried lactose.