ABSTRACT

Process Analytical Technology Initiative. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 Sources of Variability of Process and Product Quality in Pharmaceutical Manufacturing . . . . 569

Examples Illustrating the Knowledge Pyramid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 Development of a Robust Formulation of Low Wettability Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 Development of a Robust Formulation of Low Wettability Drug during Early Preformulation Activities in Relation to Drug Load . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 Case Study-The Choice of Capsule or Tablet Formulation for Early Clinical Trials Involving Low Wettability Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 The Use of Percolation Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Case Study-Percolation Effects in Relation to Excipients Ratio and Granules Size Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 The Use of Statistical Design of Experiments and Artificial Neural Networks . . . . . . . . . . . . . . . . 572

Response Surface Methodology (RSM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 Artificial Neural Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573

Identification of Critical Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 Innovative Process Technologies for Poorly Water-Soluble Drugs and the Relevance of FDA’s PAT Initiative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 The Problem of the Intrinsic Process Variability: Heat Transfer Process in Classical Lyophilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 The Myth of the Granulation End Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Scale-Up Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576

Application of First Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 Classical Thermodynamics and the Three States of Matter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578

The Transition from the First to the Second State of Matter (Gas-Liquid) . . . . . . . . . . . . . . . . . 578 The Liquid State of Matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 The Solid State of Matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 The Difference between the Liquid and Solid State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581

The Particulate State of Matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 Case Study-The Compression of a Powder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 Case Study-The Pressure Susceptibility χp of a Powder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583

9644: “9644_c020” — 2007/11/21 — 11:55 — page 568 — #2

Flow of a Powder from a Hopper . . . . . . . . . . . . . . . . . . 584 Flow of Powder-The Use of Fick’s Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586

The majority of pharmaceutical processes used in solubilization involve powders. For example, particle size reduction can resolve dissolution problems related to poor solubility. Micronized drugs and aerosols are produced as very fine particles in order to improve the bioavailability of insoluble compounds (Lee et al., 2000). Novel technologies such as fluidized bed systems operating under vacuum conditions and atmospheric spray-freeze drying can produce free-flowing powders, which is important in the manufacture of granules of low solubility drugs (Leuenberger and Kocova El-Arini, 2000). The progress made in nanoscience can lead to the manufacture of extremely small particles with fascinating special physical properties, which can improve dramatically the behavior of water-insoluble compounds (Rocco, 2000).