This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more "drug-like." ADME is all about "a day in the life of a drug molecule'' (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (pKa), oil-water partition coefficients (log P/log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA).

These physical parameters form the major components of physicochemical profiling (the "A" in ADME) in the pharmaceutical industry, from drug discovery through drug development. But, there are opportunities to apply the methodologies in other fields, particularly the agrochemical and environmental industries. Also, new applications to augment animal-based models in the cosmetics industry may be interesting to explore.

The author has observed that graduate programs in pharmaceutical sciences often neglect to adequately train students in these classical solution chemistry topics. Often young scientists in pharmaceutical companies are assigned the task of measuring some of these parameters in their projects. Most find the learning curve somewhat steep. Also, experienced scientists in midcareers encounter the topic of physicochemical profiling for the first time, and find few resources to draw on, outside the primary literature.

The idea for a book on the topic has morphed through various forms, beginning with focus on the subject of metal binding to biological ligands, when the author was a postdoc (postdoctoral fellow) in Professor Ken Raymond's group at the University of California, Berkeley. When the author was an assistant professor of chemistry at Syracuse University, every time the special topics course on speciation analysis was taught, more notes were added to the ''book.'' After 5 years, more than 300 pages of hand-scribbled notes and derivations accumulated, but no book emerged. Some years later, a section of the original notes acquired a binding and saw light in the form of Applications and Theory Guide to pH-Metric pKa and log P Measurement [112] out of the early effort in the startup of Sinus Analytical Instruments Ltd., in Forest Row, a charming four-pub village at the edge of Ashdown Forest, south of London. At Sinus, the author was involved in teaching a comprehensive 3-day training course to advanced users of pKa and log P measurement equipment manufactured by Sirius. The trainees were from pharmaceutical and agrochemical companies, and shared many new ideas during the courses. Since the early 1990s, Sirius has standardized the measurement of pKa values in the pharmaceutical and agrochemical industries. Some 50 courses later, the practice continues at another young company, pION, located along hightech highway 128, north of Boston, Massachusetts. The list of topics has expanded since 1990 to cover solubility, dissolution, and permeability, as new instruments were developed. In 2002, an opportunity to write a review article came up, and a bulky piece appeared in Current Topics in Medicinal Chemistry, entitled ''Physicochem-ical profiling (solubility, permeability and charge State).'' [25] In reviewing that manuscript, Cynthia Berger (pION) said that with a little extra effort, ''this could be a book.'' Further encouragement came from Bob Esposito, of John Wiley & Sons. My colleagues at pION were kind about my taking a sabbatical in England, to focus on the writing. For 3 months, I was privileged to join Professor Joan Abbott's neuroscience laboratory at King's College, London, where I conducted an informal 10-week graduate short course on the topics of this book, as the material was freshly written. After hours, it was my pleasure to jog with my West London Hash House Harrier friends. As the chapter on permeability was being written, my very capable colleagues at pION were quickly measuring permeability of membrane models freshly inspired by the book writing. It is due to their efforts that Chapter 7 is loaded with so much original data, out of which emerged the double-sink sum-Pe PAMPA GIT model for predicting human permeability. Per Nielsen (pION) reviewed the manuscript as it slowly emerged, with a keen eye. Many late-evening discussions with him led to freshly inspired insights, now embedded in various parts of the book.

The book is organized into eight chapters. Chapter 1 describes the physico-chemical needs of pharmaceutical research and development. Chapter 2 defines the flux model, based on Fick's laws of diffusion, in terms of solubility, permeability, and charge state (pH), and lays the foundation for the rest of the book. Chapter 3 covers the topic of ionization constants—how to measure pKa values accurately and quickly, and which methods to use. Bjerrum analysis is revealed as the ''secret weapon'' behind the most effective approaches. Chapter 4 discusses experimental methods of measuring partition coefficients, log P and log D. It contains a description of the Dyrssen dual-phase potentiometric method, which truly is the ''gold standard'' method for measuring log P of ionizable molecules, having the unique 10-orders-of-magnitude range (log P from —2 to +8). High-throughput methods are also described. Chapter 5 considers the special topic of partition coefficients where the lipid phase is made of liposomes formed from vesicles made of bilayers of phospholipids. Chapter 6 dives into solubility measurements. A unique approach, based on the dissolution template titration method [473], has demonstrated capabilities to measure solubilities as low as 1 nanogram per milliliter (ng/mL). Also, high-throughput microtiter plate UV methods for determining ''thermodynamic" solubility constants are described. At the ends of Chapters 3-6, an effort has been made to collect tables of critically-selected values of the constants of drug molecules, the best available values. Chapter 7 describes PAMPA (parallel artificial membrane permeability assay), the high-throughput method introduced by Manfred Kansy et al. of Hoffmann-La Roche [547]. Chapter 7 is the first thorough account of the topic and takes up almost half of the book. Nearly 4000 original measurements are tabulated in the chapter. Chapter 8 concludes with simple rules. Over 600 references and well over 100 drawings substantiate the book.

A. Avdeef

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