(320f) High Drug Loading High Shear Wet Granulation

High shear wet granulation is one of the most common technologies for pharmaceutical formulation. Traditionally, when drug loading ranged from 0.1% to 50%, the excipient properties have a major impact on the granulation process and ensure process robustness. However, recently there is an increased demand for high drug loading to support high dose or fixed-dose combination formulation development. With extremely high drug loading, e.g. > 80%, the granulation process becomes less understood as API (active pharmaceutical ingredient) properties dominate performance. In this work, we propose a new methodology that enables development of high drug load high shear wet granulation formulations. The key to this new methodology is to examine the correlation between the API properties and granulation attributes, so that excipients will only be added when improvement of product performance is needed. To evaluate this approach, three model compounds with different properties, such as particle size, wettability, and solubility, were selected for the study. The model compounds were granulated at drug loadings above 90%, with or without a polymeric binder, and using 1% sodiumlaurylsulfate water solution at a range of granulation fluid levels. Granule size distribution, granule strength, flow, dissolution, and compactibility were characterized. Some selected granulation samples were further compressed into tablets with or without extragranular excipients. Tablets performance was mainly evaluated with in-vitro dissolution profiles, or further tested for in-vivo dog PK studies. The findings of the study are as follows: (1) All the model compounds studied could be granulated without any binder, but the granule strength and compactibility were unsatisfactory; (2) The polymeric binders significantly improved the granule strength, dissolution, flowability, and compactibility, especially for the poor to medium soluble compounds; (3) Formulations with polyvinylpyrrolidone as the polymeric binder displayed the best overall performance; (4) Extragranular addition of excipients could effectively modify formulation as needed, which greatly increased the compatibility between excipients and API. The methodology for an effective development of high drug loading wet granulation based on the formulation components and the product attributes will be discussed.