Brock C. Roughton

Simultaneous design of ionic liquid entrainers and energy efficient azeotropic separation processes

Abstract A methodology and tool set for the simultaneous design of ionic liquid entrainers and azeotropic separation processes is presented. By adjusting the cation, anion, and alkyl chain length on the cation, the properties of the ionic liquid can be adjusted to design an entrainer for a given azeotropic mixture. Several group contribution property models available in literature have been used along with a newly developed group contribution solubility parameter model and UNIFAC model for ionic liquids (UNIFAC-IL). For a given azeotropic mixture, an ionic liquid is designed using a computer-aided molecular design (CAMD) method and the UNIFAC-IL model is used to screen design candidates based on minimum ionic liquid concentration needed to break the azeotrope. Once the ionic liquid has been designed, the extractive distillation column for the azeotropic mixture is designed using the driving force method with a new proposed feed stage scaling to minimize energy inputs. Along with the distillation column, an ionic liquid recovery stage is designed and simulations are used to determine the overall heat duty for the entire process for the best ionic liquid candidates. Use of a designed ionic liquid reduces material and energy requirements when compared to an ionic liquid known to experimentally break a given azeotrope but not designed using CAMD methods. The acetone–methanol and ethanol–water azeotropes are provided as examples.

Use of glass transitions in carbohydrate excipient design for lyophilized protein formulations

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.

Optimizing Protein-Excipient Interactions for the Development of Aggregation-Reducing Lyophilized Formulations

Abstract As protein drugs become increasing popular therapeutic approaches, formulations must be developed to ensure stability of the final drug product. Lyophilization, or freeze - drying, is an approach commonly used to produce stable protein drugs, yet protein aggregation may still occur in lyophilized formulations. Excipients in the formulation may be selected to reduce the propensity of a protein to aggregate through interaction with aggregation prone regions. In the following work, molecular docking simulations were used to predict the regions on a protein where different excipients were most likely to interact. Simulation results compared variably with experimental hydrogen/deuterium exchange experiments used to determine regions of protein-excipient interactions. The results were used to design formulations for lyophilized calmodulin (PID #1CLL). Sugar and surfactant pairs were selected that would maximize protection of different aggregation prone regions through direct interactions.

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

Dental adhesive resin undergoes phase separation during its infiltration through the wet demineralized dentin and it has been observed previously that the hydrophilic-rich phase is a vulnerable region for failure due to the lack of photo-polymerization and crosslinking density. The lack of photo-polymerization is mostly due to the partitioning of photo-initiators in low concentrations within this phase. Here, a computational approach has been employed to design candidate water compatible visible light photosensitizers which could improve the photo-polymerization of the hydrophilic-rich phase. This study is an extension of our previous work. QSPRs were developed for properties related to the photo-polymerization reaction of the adhesive monomers and hydrophilicity of the photosensitizer using connectivity indices as descriptors. QSPRs and structural constraints were formulated into an optimization problem which was solved stochastically via Tabu Search. Four candidate photosensitizer molecules have been proposed here which have the iminium ion as a common feature.

Computational Molecular Design of Water Compatible Dentin Adhesive System

Abstract The objective of this work is to develop a framework to a design dentin adhesive system for water compatibility and efficient photo-polymerization applying computer aided molecular design. A dentin adhesive system consists of monomers and photo-initiators which trigger a photo-polymerization reaction when exposed to visible light. In this study a water compatible visible light photosensitizer was designed for dental applications. Quantitative structure property relationships (QSPRs) were developed for relevant properties (octanol/water partition coefficient and molar extinction coefficient) using molecular descriptors. The QSPRs are combined with structural constraints to form a MINLP, which is then solved to near optimality using Tabu search to generate novel candidate photosensitizer molecules with desired properties. Tabu search, a heuristic optimization method, does not yield globally optimal solutions for MINLPs, but it is an efficient and practical method for solving general combinatorial optimization problems. This framework will provide insight regarding possible functional groups for developing water-compatible visible light photosensitizers for dentin adhesive systems.

Designing Optimum Protein-Excipient Interactions using Molecular Docking Simulations

Abstract As the market for protein drugs is constantly increasing, methods to ensure the stability of the final drug formulation are needed. The choice of excipient in the protein drug formulation can lower the probability of protein aggregation through interactions between the excipient and aggregation prone regions (hot spots) on the protein. The following work uses molecular docking simulations to predict protein excipient interaction regions on the protein and then compares the results with hydrogen- deuterium exchange experiment results. A method using a combination of computer- aided molecular design and molecular docking simulations is proposed to find an optimum excipient minimizing aggregation probability for any particular protein.