We investigated the spheronization of micronized drug powder using a mechanical powder processor that can produce spherical particles with a drug content of 100%. Theophylline anhydrate and monohydrate were micronized through a jet-mill process and then subjected to mechanical treatment The anhydrate was very slightly agglomerated and was not converted into spherical particles, whereas the monohydrate was remarkably agglomerated and yielded spheres at the end of processing. These results indicate that the spheronization of theophylline monohydrate powder is more likely to occur than that of theophylline anhydrate powder, despite these materials exhibiting similar powder cohesiveness (which is believed to determine the success of mechanical spheronization). Consequently, theophylline monohydrate may be spheronized by driving factors other than the native cohesiveness of the material. Crystalline analysis and water determination data showed that part of the monohydrate powder was dehydrated during processing and transformed into anhydrate, indicating the release of free water during mechanical treatment Furthermore, the presence of solid bridge between primary particles of the spheronized theophylline monohydrate suggests that the liquid bridge is generated during the processing and results in the spheronization. Therefore, the spheronization of theophylline monohydrate is due to the agglomeration through the water released by the dehydration. (C) 2018 Elsevier B.V. All rights reserved.