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.

On the Possibility of Indirect Determination of the Glass Transition Temperature of Proteins from Viscosity Measurements and Avramov's Model

“…In other words, the glass transition temperature of the protein is the temperature in which its properties change from liquid-like to solid-like. In the literature of recent years can be seen increasing interest to glass transition phenomenon of biopolymers such as proteins or polysaccharides (Grasmeijer et al, 2013;Marsh et al, 2013;Khatkar et al, 2013;Roughton et al, 2012;García et al, 2012;Panagopoulou et al, 2011;Rodríguez Furlán et al, 2011;Hernández et al, 2011;Khodadadi et al, 2010;Jansson & Swenson, 2010). The glass transition temperature of proteins is determined primarily using calorimetric and rheological measurements and dielectric spectroscopy.…”

Protein aggregation and lyophilization: Protein structural descriptors as predictors of aggregation propensity

“…Perhaps more importantly, the correlations are limited in that the effects of excipients on aggregation are not included quantitatively, since the number of excipients tested was small. Previous studies by the authors have related protein aggregation on lyophilization to molecular descriptors of structure for carbohydrate excipients (Roughton, Topp, & Camarda, 2012). Broader correlations that address both protein structure and excipient effects would be more useful in formulation design, and could direct the development of new excipients that better prevent aggregation for a given protein.…”

Computer-aided molecular design of water compatible visible light photosensitizers for dental adhesive

“…Connectivity indices have been successfully used in the past to design pharmaceuticals, environmentally benign catalyst, cross-linked polymer etc. (Chavali et al ., 2004; Eslick et al ., 2009; Roughton et al ., 2012b; Siddhaye et al ., 2000). Roughton et al .…”

“…Roughton et al . employed connectivity indices to estimate properties such as glass transition temperature, Gordon-Taylor constant for carbohydrate excipient (Roughton et al ., 2012b). …”

“…Roughton et al . have used Tabu search to design carbohydrate excipient to minimize protein aggregation (Roughton et al ., 2012b). Camarda et al .…”