Chapter 4 - API Solid-Form Screening and Selection

Abstract

Most active pharmaceutical ingredients (APIs) are solid in nature and could exist in many forms that vary significantly in their properties, leading to different physical, chemical, mechanical, and biopharmaceutical properties. The ideal solid form of APIs is one that cannot only be manufactured reproducibly, characterized in detail with respect to identity and stability, but also be formulated as a drug product (DP) that meets the intended target product profile. Therefore, screening and selection of the API solid form is a critical component in drug development that influences quality, performance, manufacturing process, and robustness of a drug substance and DP. Solid forms of APIs can exist as crystalline forms, including polymorphs, hydrates, solvates, cocrystals, and salts, as well as amorphous forms. The formation of salts, cocrystals, solvates, and hydrates as well as the existence of polymorphs is rarely predictable. Hence, the aim of solid-form screening and selection is to identify and characterize as many forms as possible and select a form with the optimal physical, chemical, and biopharmaceutical properties. Screening may be manual or automated in a high-throughput fashion and utilizes variety of techniques such as crystallization, precipitation, and thermal techniques. The execution of API solid-form selection strategy involves implementation of a multistep process including a broad screen for solid forms, followed by characterization including thermodynamics and kinetics, accelerated stability testing, solubility/dissolution testing, and, if necessary, in-silico and in vivo studies for pharmacokinetics evaluation in a DP. A thorough solid-form screening, characterization, and selection are essential to maximize the potential of enabling a drug candidate from a patient, quality, and manufacturing perspectives.