Objective: Granulated pellet-containing tablets (GPCT) prepared by a novel granulation technique showed better uniformity and compressibility over traditional pellet-containing tablets (PCT). The superiority of GPO' was mainly due to the excipient layer, which was laid over the coated pellets and modified the surface of pellets with increased roughness. Microcrystalline cellulose (MCC) was the main layering component which greatly influenced the stability of GPCT in storage, so was the additional excipients. The purpose of this study was to investigate the influence of excipient layer on the stability of GPO'. Methods: GP were prepared by layering the combination of various excipients with MCC over the coated pellets, and further compressed into GPO'. The drug release profiles from the coated pellets, GP, and GPO' were compared, and the drug degradation rate in GP and GPO' were evaluated under high temperature, strong light, and high humidity conditions for up to 10 days. Results: The drug content in GP and GPO' was above 97% after storage under high temperature and strong light, but dropped to 93%-96% under high humidity. The drug degizdation rate in GP followed the order of excipient hygroscopicity as PVPP > CMC-Na > Lactose, while GPO' with PVPP showed the least drug degradation, suggesting the stability of GPO' was mainly determined by the excipient compressibility. Conclusions: All formulations under high temperature and strong light were stable, indicating the influence of temperature and light could be ignored. Under high humidity conditions, the drug degradation in GP was in accordance with the excipient hygroscopicity, while it was dominated by excipient compressibility in GPO'. Therefore, the binary mixture of MCC and PVPP with the best compressibility may be ideal layering excipients to prepare acceptable GPO' for humidity sensitive drugs. (C) 2014 Published by Elsevier B.V.