Akira Takada1, Steven L Nail, Masakatsu Yonese. 1. Pharmaceutical Development Laboratories, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan. a.takada@ono.co.jp
Abstract
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 degrees and 17.2 degrees 2theta for the alpha polymorph, at 14.6 degrees and 23.4 degrees 2theta for the beta polymorph and at 9.7 degrees 2theta for the delta polymorph. The addition of ethanol to the initial solutions resulted in only a peak at 9.7 degrees 2theta, indicating the presence of only the delta 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 alpha 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 degrees C to 160 degrees C, which corresponded to the transition of the delta form to alpha or beta 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 delta 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.
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 degrees and 17.2 degrees 2theta for the alpha polymorph, at 14.6 degrees and 23.4 degrees 2theta for the beta polymorph and at 9.7 degrees 2theta for the delta polymorph. The addition of ethanol to the initial solutions resulted in only a peak at 9.7 degrees 2theta, indicating the presence of only the delta 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 alpha 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 degrees C to 160 degrees C, which corresponded to the transition of the delta form to alpha or beta 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 delta 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.