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5078536 
Journal Article 
Freeze-drying from organic co-solvent systems, part 2: process modifications to reduce residual solvent levels and improve product quality attributes 
Kunz, C; Schuldt-Lieb, S; Gieseler, H 
2019 
Yes 
Journal of Pharmaceutical Sciences
ISSN: 0022-3549
EISSN: 1520-6017 
108 
399-415 
English 
The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various cosolvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low-melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation. 
freeze-drying/lyophilization; calorimetry (DSC); X-ray powder diffraction; organic solvents; residual solvent 
IRIS
• tert-Butanol
     Excluded/ Not on Topic
          Methodology/Solvent
     LitSearch: Jan 2017 - July 2019
          PubMed
OPPT REs
• OPPT_1,4-Dioxane_D. Exposure
     Total – title/abstract screening
          Supplemental Search
               Consumer Use