Srinivas Tummala

An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design

In this case study, we present an approach for employing modeling to help define the design space for a reaction with potential to generate an impurity that could impact the quality of an API. Our approach broadly consisted of (1) evaluating the reaction parameters that can affect the critical impurity level to develop appropriate assumptions for a mechanistic model, (2) developing and evaluating a mechanistic model to predict the formation of the critical impurity, (3) defining a design space based on the model output to reduce in practice the acceptable parameter space to a practical number of parameters, and (4) verifying the design space through experimental testing. This work resulted in a verified design space that can be practically employed and includes wide parameters ranges for manufacturing flexibility.

Model-Guided Design Space Development for a Drug Substance Manufacturing Process

This case study outlines an application of quality by design principles to a drug substance manufacturing process. A hybrid process chemistry model consisting of mechanistic and empirical components was developed to guide the selection and verification of a design space. A multistaged experimental plan was employed to address specific goals at each stage of model development and design space selection. In addition to the multivariate evaluation of process parameters, accounting for the quality attributes of input materials was shown to be an important consideration when choosing a design space. The merits of a model-guided approach to selecting an invariant, experimentally verified design space (as opposed to a fully model-defined dynamic design space) are discussed.

A Mechanistic Study on the Amidation of Esters Mediated by Sodium Formamide

Kinetic and computational studies on the amidation of esters with mixtures of formamide and sodium methoxide are described. Rate studies are consistent with a fast deprotonation of formamide followed by two reversible acyl transfers affected by solvent participation. MP2 calculations suggest that the first acyl transfer between the ester and sodium formamide is rate-determining. The transition structures leading to the formation and collapse of the first tetrahedral intermediate are calculated to be isoenergetic.

The effect of additives on the zinc carbenoid-mediated cyclopropanation of a dihydropyrrole.

The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Brønsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.