Ever-Increasing Role of Computational Tools in Solid-State Pharmaceutics: Advancing Drug Development with Enhanced Molecular Understanding and Risk Assessment

The field of solid-state pharmaceutics comprises a broad range of investigations into various structural aspects of pharmaceutical solids, establishing a rational structure–property correlation. These solid systems allow the tunability of the physicochemical properties, such as solubility and dissolution, which in turn influence the pharmacokinetic and pharmacodynamic parameters of the active pharmaceutical ingredient (API). Hence, the study of physical characteristics of an API, e.g., different crystalline vs amorphous forms, molecular complexes such as solvates, cocrystals, coamorphous and polymeric dispersions, etc., along with an understanding of interconversion of one form into the other forms, a basis for successful product development. A product’s time to market is typically prolonged by the time it takes to complete the development aspects of the product compared to the time required for lead optimization, i.e., for identification of the right chemical entity. Recent advancements in computational techniques have revolutionized the field of solid-state pharmaceutics in understanding molecular-level mechanisms while significantly cutting down the time and resources needed for drug development. Over the years, there have been increasing contributions of the computational tools demonstrated by the successful implementation of computationally obtained prediction models validated and benchmarked against conventional experimental results. Examples include application of Density Functional Theory, molecular dynamics, and artificial neural networks to screen coformers, polymers for cocrystallization, and ASD formation; crystal structure prediction to select correct polymorphs with desired characteristics, and also to predict interactions with excipients. It has been proven that computational tools can effectively troubleshoot and address issues associated with the translational output of solid-state pharmaceutics. In this article, we present a series of case studies highlighting the use of modern computational techniques applied to critical stages of API, preformulation, and formulation developments contributing to accelerated drug development, while conserving on chemicals, solvents, and man-hours. Crucially, a concise sequential workflow is presented that explains the benefits of each of the computational methods in the toolbox, with the goal of assisting the readers in the specific application of these techniques, as per their requirements in the solid-state pharmaceutics domain.