Several methods have been employed to enhance the bioavailability of drugs with low aqueous solubility including micronization, dispersion of the drug in solid carriers, and chemical modifications. Among these methods, solid dispersions have received extensive attention as a potential approach to increase the dissolution rate. However, there are still some limitations that restrict the application of this technique for drug formulations. One main concern is the reproducibility of the physicochemical and microstructural properties of the solid dispersions during scale-up and storage. Additionally, the mechanism by which the dissolution rate is enhanced is still unclear; this is likely to be closely related to the solid dispersion microstructure. In this research, chlorpropamide (CPM) was chosen as the model drug. Mixtures of CPM and polyethylene glycol (PEG) were melted and recrystallized at different temperatures, and the dispersions were stored at low relative humidity in desiccators. The crystallization behavior of both CPM and PEG, as well as the microstructure of CPM within PEG matrix was investigated. Polymorph B was identified in dispersions from the powder X-ray diffraction (PXRD) pattern, while the commercial form of CPM is polymorph A. PEG has a typical spherulitic structure after recrystallization, and CPM-PEG dispersions showed irregular structure at a 40% CPM loading. Small angle X-ray scattering demonstrated that, when CPM was present within the PEG matrix, the long period (L) of PEG changed, indicating that CPM may exist within the interlamellar regions of the PEG matrix.