Influence of Ethanol on Physical State of Freeze-Dried Mannitol

Purpose The purpose of this study is to characterize freeze-dried mannitol prepared from an ethanol-containing solution as a function of the ethanol ratio, mannitol concentration, and annealing in the freeze-drying cycle. Methods The characteristics of the freeze-dried mannitol were evaluated by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The reconstitution time was measured for the freeze-dried solids as well as the residual moisture and ethanol by Karl–Fischer titration and gas chromatography, respectively. Results The XRD pattern of 5% ( w / v ) mannitol freeze-dried from aqueous solution with no annealing cycle showed all the five characteristic peaks at 13.6° and 17.2° 2 θ for the α polymorph, at 14.6° and 23.4° 2 θ for the β polymorph and at 9.7°2 θ for the δ polymorph. The addition of ethanol to the initial solutions resulted in only a peak at 9.7° 2 θ , indicating the presence of only the δ polymorph, regardless of the ethanol ratio in the initial solutions used [10, 20, 30, and 40% ( v / v )]. However, annealing during freeze-drying influenced the XRD pattern; in particular, for the solid prepared from the 10% ethanol solution. Annealing of the 10% ethanol solution promoted the formation of the α polymorph and produced a different peak that might be attributable to another polymorph. In DSC thermograms, an endotherm and a subsequent exotherm were found in the temperature range of 150°C to 160°C, which corresponded to the transition of the δ form to α or β forms. The magnitude of this transition was smaller as the ethanol ratio increased for the solids from ethanol-containing solutions with an annealing cycle. In other words, annealing of the ethanol-containing solutions promoted δ polymorph formation in the lyophiles. In addition, the mannitol concentration affected the polymorphism in freeze-dried solids prepared from aqueous and 10% ethanol solutions. Addition of ethanol in the initial solution, in particular, at a lower ethanol level (10% v / v ), and a higher concentration of mannitol could also promote the generation of lumps in freeze-dried solids during reconstitution, and result in longer reconstitution time. The residual moisture levels were less than 0.5%, and residual ethanol levels were less than 0.1%, irrespective of the formulation used. Conclusions The physical state and reconstitution time of the freeze-dried mannitol appears to be a complex function of the ethanol and mannitol concentrations in the initial solution before freeze-drying and of annealing during the freeze-drying process.