(580a) Transforming Pharmaceutical Development and Manufacturing with Molecular Computations

A great amount of resources have gone into molecular computational approaches for the rational discovery of new pharmaceutical compounds with marked success.  However, little emphasis has been placed on molecular computational approaches for the rational design of formulations (development) and of pharmaceutical processes (manufacturing).  This is despite that fact that total costs of these exceed that of discovery by a large fraction and industry-wide are over $150 billion per year.

We discuss two directions in which we have applied molecular computations to play a significant role in pharmaceutical development and manufacturing.  One is in the area of stabilization of therapeutic antibodies.  These molecules are inherently unstable with respect to aggregation, and we have developed new algorithms to predict these instabilities and identify sites responsible for them that can be mutated out to lead to enhanced stability. The second area is in small molecule pharmaceutical crystallization.  Crystallization is a major part of both development and manufacturing, but it is currently more an art than a science.  We present new algorithms and their application to understand the mechanisms of nucleation and crystallization and apply them to model pharmaceutical systems and therein develop better products and manufacturing processes.