Integrating Computational Materials Science Tools in Form and Formulation Design

INTEGRATING COMPUTATIONAL MATERIALS SCIENCE TOOLS IN FORM AND FORMULATION DESIGN 

Joseph F. Krzyzaniak, Paul A. Meenan Cheryl L. Doherty, Klimentina Pencheva Suman Luthra, and Aurora Cruz-Cabeza  

Computational Pharmaceutical Solid State Chemistry, First Edition. Edited by Yuriy A. Abramov. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

While the goal of the solid-state chemist is to select the thermodynamically stable form to be used in the development of a drug product that provides robust performance, stability, and manufacturability, it is important to consider the quote from Maria Kuhnert-Brandstatter (1975) Probably every substance is potentiaUy polymorphic. The only question is whether it is possible to adjust the external conditions in such a way that polymorphism can be realized or not. It is clear that the environmental conditions of an API solid form, at normal manufacturing and storage condition, are very different from the conditions that the API sohd form is exposed to in the drug product The formulation can alter the environment in such a way that the thermodynanucally stable form becomes metastable. This is a common occurrence when thermodynamically stable anhydrous forms are formulated to prepare an aqueous-based dosage form, in which a precipitation of a hydrate with lower solubility is observed [9]. 

Over the past few years, materials scientists have designed and conducted research to determine the stable form in the conditions of the formulated dosage form. Luthra et al. identified that the thermodynamically stable form, anhydrous crizotinib free base, converted to a qnatemary complex (API, phosphate, water, sucralose) in the formulated oral solution in which precipitation was observed [9]. This spurred the design of new solid form/polymorph investigation designated as the Formulation Form Screen. In this case as well as research published by Arora et al. [10, 11] and Bak et al. [12], unintended cocrystal formation occurred between the stable form of the API and the formulation components. As the number of variables and conditions exponentially increase as the stable API form is exposed to a formulated environment, there becomes a need to develop new approaches to test the reactivity of the API with its formulation components. 

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