A new methodology for high drug loading wet granulation formulation development.

A new methodology that enables efficient and rapid development of high drug load (>85%) high shear wet granulation formulations is proposed and tested in this work. Correlations between the API properties, the binder types, the granulation fluid levels, and the product attributes revealed in course of the study are discussed. The key feature of the methodology is that an excipient is added to the formulation only when it is demonstrated that it is required to improve processability or performance of the formulation. To evaluate this approach, three compounds: simvastatin, etoricoxib, and metformin hydrochloride were selected as model drug substances. These compounds differ significantly with respect to their particle size distributions, wettability, and solubility. The compounds were granulated using a range of granulation fluid levels, with or without a polymeric binder. Granule size distribution, strength, flowability, dissolution, and compactibility were characterized. Select granulations were further compressed into tablets, both "as-is" and with addition of extragranular excipients. One formulation was also investigated in an in vivo dog PK study. The study demonstrated that using the methodology, high drug load formulations with satisfactory attributes could be successfully developed for all three model compounds. Applicability and benefits of the proposed methodology are discussed.