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The purpose of this study was to elucidate how co-solutes affect the crystallization of small solute molecules during freeze-drying and subsequent storage. Crystallization profiles of myo-inositol and its mixture with dextran 40k in frozen solutions and dried solids were assessed by thermal analysis (DSC), powder-X-ray diffraction, and simultaneous DSC and PXRD analysis. Higher mass ratios of dextran maintained myo-inositol in the non-crystalline mixture state, in frozen solutions, during freeze-drying process, and exposure of dried solids to higher temperatures. Co-lyophilization with a lower mass ratio of dextran resulted in solids containing a variety of myo-inositol crystal forms and crystallinity depending on the composition and thermal history of the process. Heating of some inositol-rich amorphous solids showed crystallization of myo-inositol in the metastable form and its transition to stable form before melting. Heat-treatment of inositol-rich frozen solutions resulted in high crystallinity stable-form inositol solids, leaving dextran in the amorphous state. Sufficient direct molecular interactions (e.g., hydrogen bonding) should explain the stability of dextran-rich amorphous solids. Optimizing solute composition and processes should be a potent way to control crystal form and crystallinity of components in freeze-dried formulations.