Particle Engineering: Fundamentals of Particle Formation and Crystal Growth
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10/31/2006
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Particle Engineering: Fundamentals of Particle Formation and Crystal Growth Alfred Y. Lee and Allan S. Myerson Abstract The engineering of particles with customized properties optimized for dosage form manufacture (tablet, capsule, ointment, etc.) has long been a goal of the pharmaceutical industry. Particles can be designed through modification in the size, morphology, and packing arrangement of the solids. The most common approach in achieving this is through crystallization. In this bottom-up process, the two main steps, nucleation and crystal growth, both play a decisive role in shaping the quality of the final crystalline product. In this review, the role of nucleation and crystal growth in controlling particle properties is discussed, and examples are provided that demonstrate the variation in solid-state properties as a function of size, habit (morphology), and internal structure of the particles. In addition, the role of particle properties in product performance and dosage form development of pharmaceuticals is also discussed. Keywords: crystal growth, morphology, nucleation, particle.
Introduction Solution crystallization has been described as the most important unit operation in the pharmaceutical industry.1 More than 90% of all pharmaceutical products contain active pharmaceutical ingredients and/or excipients (inactive substances that are included in the manufacturing process or are contained in the finished form) in the crystalline state.2 Crystallization involves two distinct steps: nucleation, which corresponds to the birth of a new crystal, and crystal growth, which is the evolution of nuclei into mature crystals. Crystals can be generated in a wide variety of sizes, shapes, and lattice structures. Each of these characteristics can affect the chemical and physical properties of the solid. For instance, it is essential to consistently produce one particular crystal form to ensure that the bioavailability and stability of the drug substance are uniform. The control of the crystal shape is also vital, because particle morphology can affect post-crystallization processes such as drying, filtration, and milling.
MRS BULLETIN • VOLUME 31 • NOVEMBER 2006
The design of organic solids with desired chemical and physical properties is often referred to as crystal engineering.3 During the past three decades, the field of crystal engineering has gained momentum4 and has been encompassed in a wide range of disciplines, including supramolecular chemistry and pharmaceutical materials science. This article highlights how the chemical, physical, and mechanical properties of drug substances can be enhanced through variations in solid-state packing arrangements, morphological crystal engineering, and particle size control.
Nucleation Nucleation is the first step in the crystallization process. It may occur spontaneously or be induced by a foreign substance, surface, or external field (electric or magnetic). Nucleation can be classified as primary or secondary. Secondary nucleation in
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