Content uniformity (CU) is a crucial evaluation factor, especially for low-dose oral formulations. Spray-dried monohydrate lactose is generally recommended for direct compression/dry granulation, but we observed that it showed advantages in the wet granulation tableting method for low-dose tablet formulation. In this study, several commercial brands of lactose were selected and suitable tableting methods were applied to a low-dose oral formulation of pentyloxyl paliperidone derivative (PD6) with drug loading at 1.5% (w/w) and lower. The effects of spray-dried/sieved/milled monohydrate and anhydrous lactose on CU were investigated. Granules/powder mixtures were studied in terms of their size distribution, repose angle, flowability and bulk/tapped density. In addition, SEM, DSC, CU, tablet weight, hardness, friability and in vitro cumulative release profiles were investigated. The relationships between the powder characteristics and CU results were also studied. Wet granules using spray-dried lactose monohydrate presented satisfied flowability, fair compressibility and a low particle size span compared with all the other tested types of lactose. The product tablets also presented optimal evaluation results for 1.5% (w/w) drug loading (CU = 12.22) and displayed good repeatability among 100 g to 2 kg levels. Further study using another two brands of lactose produced similar results, indicating using spray-dried monohydrate lactose in wet granulation may apply universally to low-dose formulations. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.