Control of physical forms of pharmaceutical substances

Predictive control of the physical forms of drug and excipient materials is of great relevance in the contexts of patent protection, process development, and product specification in the pharmaceutical industry (1). Pharmaceutical solids exist broadly as either crystalline or amorphous forms. Perfect crystalline substances are rare, and materials are often characterized by imperfections (defects) of varying degrees in their crystal structures, depending on their formation or treatment history. In addition, certain materials can exist in grossly different crystal forms (e.g., polymorphs, solvates, or hydrates) under defined conditions of pressure, temperature, and/or relative humidity. Being different in free energy and thermodynamic activity, all these structural modifications, be they due to different densities of crystal imperfections or to grossly different crystal structures, are generally distinguishable by their differences in physical properties, such as hardness, melting point, solubility, and dissolution rate, all of which can impact significantly the manufacturing process as well as the in vivo performance of the finished drug products. Consequently, it has always been the goal of pharmaceutical formulators to seek effective means of controlling the physical forms of pharmaceutical raw materials, which is important not only to ensure consistency and predictability of product performance but also to satisfy the related drug regulatory requirements.