Industrial application of heat- and mass balance model for fluid-bed granulation for technology transfer and design space exploration.

This work demonstrates the application of state-of-the-art modeling techniques in pharmaceutical manufacturing for fluid bed granulation at varying scales to successfully predict process conditions and ultimately replace experiments during a technology transfer of five products. We describe a mathematical model able to simulate the time-dependent moisture profile in a fluid bed granulation process. The applicability of this model is then demonstrated by calibrating and validating it over a range of operating conditions, manufacturing scales, and formulations.

Modeling of pan coating processes: Prediction of tablet content uniformity and determination of critical process parameters.

We developed an engineering model for predicting the active pharmaceutical ingredient (API) content uniformity (CU) for a drug product in which the active is coated onto a core. The model is based on a two-zone mechanistic description of the spray coating process in a perforated coating pan. The relative standard deviation (RSD) of the API CU of the coated tablets was found to be inversely proportional to the square root of the total number of cycles between the spray zone and drying zone that the tablets undergo.

Experimental and model-based approaches to studying mixing in coating pans.

The focus of this study was the determination of mixing patterns and rates inside a cylindrical coating pan. The research for this study was divided into two parts. The first part examined the mixing pattern and the movement of tablets inside of a coating pan experimentally.

Effects of chain length on the aggregation of model polyglutamine peptides: molecular dynamics simulations.

Aggregation in the brain of polyglutamine-containing proteins is either a cause or an associated symptom of nine hereditary neurodegenerative disorders including Huntington's disease. The molecular level mechanisms by which these proteins aggregate are still unclear. In an effort to shed light on this important phenomenon, we are investigating the aggregation of model polyglutamine peptides using molecular-level computer simulation with a simplified model of polyglutamine that we have developed.

Spontaneous formation of annular structures observed in molecular dynamics simulations of polyglutamine peptides.

Annular structures have been observed experimentally in aggregates of polyglutamine-containing proteins and other proteins associated with diseases of the brain. Here we report the observation of annular structures in molecular-level simulations of large systems of model polyglutamine peptides. A system of 24 polyglutamine chains 16 residues long at a concentration of 5 mM spontaneously formed large beta sheets which curved to form tube-like annular structures that resemble beta barrels.

Side-chain interactions determine amyloid formation by model polyglutamine peptides in molecular dynamics simulations.

The pathological manifestation of nine hereditary neurodegenerative diseases is the presence within the brain of aggregates of disease-specific proteins that contain polyglutamine tracts longer than a critical length. To improve our understanding of the processes by which polyglutamine-containing proteins misfold and aggregate, we have conducted molecular dynamics simulations of the aggregation of model polyglutamine peptides. This work was accomplished by extending the PRIME model to polyglutamine.

Solvent effects on the conformational transition of a model polyalanine peptide.

We have investigated the folding of polyalanine by combining discontinuous molecular dynamics simulation with our newly developed off-lattice intermediate-resolution protein model. The thermodynamics of a system containing a single Ac-KA(14)K-NH(2) molecule has been explored by using the replica exchange simulation method to map out the conformational transitions as a function of temperature. We have also explored the influence of solvent type on the folding process by varying the relative strength of the side-chain's hydrophobic interactions and backbone hydrogen bonding interactions.