Spontaneous amorphization of ibuprofen (IB) by the coexistence of its solvent vapor and polymeric matrix, hydroxypropyl methylcellulose (HPMC), were elucidated by combining X-ray diffractometry, mid-and near-IR spectroscopy, and thermal analyses, together with the stability test of the non-crystalline IB by prolonged exposure to water vapor. The non-crystalline state of IB was achieved by the recombination of hydrogen bonds from intracrystalline ones to intermolecular ones between IB and HPMC. Coexistence of the solvent molecular species, either methanol or ethanol, significantly increased the stability of the non-crystalline states of IB. Since IB globules of 20 -50 nm were observed by TEM, IB in a non-crystalline state cannot be regarded as a perfect molecular dispersion. We therefore attributed the apparent stability increase to two aspects, i.e., (1) molecular interaction between IB and HPMC by abridging ethanol or methanol molecules via both hydrogen bonds and hydrophobic effects, and (2) retardation of nucleation and growth by suppression of IB molecular mobility by IB-HPMC network structure.