title: Use of glass transitions in carbohydrate excipient design for lyophilized protein formulations.
abstract: This work describes an effort to apply methods from process systems engineering to a pharmaceutical product design problem, with a novel application of statistical approaches to comparing solutions. A computational molecular design framework was employed to design carbohydrate molecules with high glass transition temperatures and low water content in the maximally freeze-concentrated matrix, with the objective of stabilizing lyophilized protein formulations. Quantitative structure-property relationships were developed for glass transition temperature of the anhydrous solute, glass transition temperature of the maximally concentrated solute, melting point of ice and Gordon-Taylor constant for carbohydrates. An optimization problem was formulated to design an excipient with optimal property values. Use of a stochastic optimization algorithm, Tabu search, provided several carbohydrate excipient candidates with statistically similar property values, as indicated by prediction intervals calculated for each property.
authors.affiliation: University of Kansas, Bioengineering Graduate Program, 1520 W. 15th Street, Lawrence, KS 66045, United States.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Roughton
authors.affiliation: Purdue University, Department of Industrial and Physical Pharmacy, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States.
authors.forename: E M
authors.initials: EM
authors.lastname: Topp
authors.affiliation: University of Kansas, Department of Chemical and Petroleum Engineering, 1530 W. 15th Street, Lawrence, KS 66045, United States.
authors.forename: Kyle V
authors.initials: KV
authors.lastname: Camarda
keywords: Excipient; Lyophilization; Molecular design; Protein aggregation; Stochastic optimization