Chapter 12 Impact of Solid-State Characteristics to the Physical Stability of Drug Substance and Drug Product Yushen Guo Contents 12.1 Introduction .............................................................. 242 12.2 Solid-State Characteristics and Physical Stability of Drug Substance .......................................................... 242 12.2.1 Polymorphism ...................................................... 244 12.2.2 Hydrates .......................................................... 245 12.2.3 Amorphous Form ................................................... 246 12.2.4 Solid-State Physical Change Mechanism and Stress Stability .................................................. 249 12.3 Physical Stability of Drug Products ........................................... 251 12.3.1 General Considerations .............................................. 251 12.3.2 Solid Dosage Forms ................................................. 253 12.3.3 Liquid Dosage Forms ................................................ 255 12.4 Conclusion ............................................................... 258 References ............................................................... 258 Abstract In the drug development and commercialization process, the acceptable stability of the drug substance and drug product is one of the basic requirements for clinical studies, regulatory approval, and marketing. The stability of a drug product is related not only to the intrinsic chemical stability of the drug molecule, but also to the physical forms, manufacturing processes, interactions among formulation com- ponents, container closure systems, and storage conditions. In the past two decades, there has been a significant increase in the mechanistic understanding of the solid- state characteristics of pharmaceutical systems, along with the advancement of ana- lytical techniques. Physical stability, as one of the quality attributes of drug products, should be designed into the formulation components and critical manufacturing steps using the Quality by Design (QbD) strategy to achieve intended shelf-life and Y. Guo (B ) Achaogen Inc., 7000 Shoreline Court, South San Francisco, CA 94080, USA e-mail: yguo@achaogen.com K. Huynh-Ba (ed.), Handbook of Stability Testing in Pharmaceutical Development, DOI 10.1007/978-0-387-85627-8 12, C  Springer Science+Business Media, LLC 2009 241