Formulation development and process scale up of a high shear wet granulation formulation containing a poorly wettable drug.

Aplaviroc 200 mg tablets were made by a high shear wet granulation process. A formulation and process DOE were carried out to define formulation and process parameters at pilot scale in GSKs R&D facility. During the scale up, several batches made at the production facility dissolved slower than the R&D batches. Extensive studies were conducted to examine a variety of factors to identify the root cause of this small but consistent drop in dissolution. Tablet hardness and lubrication time had a rather surprising impact on drug dissolution. Softer tablets dissolved slower despite disintegrating faster. Lubricating the granules with magnesium stearate for 3 h produced faster dissolving tablets than lubricating the granules for 3 min. Visual observations made during the dissolution trials shed some light on these surprising phenomena. As tablets disintegrated, some fragments floated to the top of the dissolution vessels and remained floating throughout the test. Due to poor wetting and lack of shear force, the drug was entrapped in these floating particles. Softer tablets and "lightly-lubricated" tablets disintegrated faster and had the floating fragments appear earlier in the dissolution trial. Sourcing of magnesium stearate may also play a role on the floating behavior.