Historically, medicines have been administered through the obvious portals following their preparation first by the shaman and then by the physician and later by the apothecary. These natural products were ingested, rubbed-in, or smoked. For the past century, the person diagnosing the disease no longer prepares the potion, eliminating, no doubt, some of the power of the placebo, and as a consequence, drug discovery, development, and manufacturing have grown into a separate pharmaceutical industry. In particular, the last 50 years have been a period of astounding growth in our insight of the molecular function of the human body. This has led to discovery of medicines to treat diseases that were not even recognized a half-century ago. This chapter reflects the role of pharmaceutics and the diversity of the approaches taken to achieve these successes, including approaches that were introduced within recent years, and describes how the role of the "industrial" pharmacist has evolved to become the technical bridge between discovery and development activities and, indeed, commercialization activities. No other discipline follows the progress of the new drug candidate as far with regard to the initial refinement of the chemical lead through preformulation evaluation to dosage-form design, clinical trial material (CTM) preparation, process scale-up, manufacturing, and then life-cycle management (LCM).
The pharmaceutical formulation was once solely the responsibility of the pharmacist, first in the drugstore and later in an industrial setting. Indeed, many of today's major drug companies, such as Merck, Lilly, Wyeth, and Pfizer components Searle, WarnerLambert, and Parke-Davis, started in the backrooms of drugstores. During the second half of the 20th century, physicochemical and biopharmaceutical principles underlying pharmaceutical dosage forms were identified and refined, thanks to the pioneering works by Higuchi,1 Nelson,2 Levy,3 Gibaldi,4 and their coworkers. Wagner,5 Wood,6 and Kaplan7 were among the earliest industrial scientists to systematically link formulation design activities and biology. Nevertheless, until recently, formulations were developed somewhat in isolation with different disciplines involved in drug development operating independently. For example, during the identification and selection of new chemical entities (NCEs) for development, not much thought was given into how they would be formulated, and during dosage-form design, adequate considerations of in vivo performance of formulations was lacking. Wagner5 first termed our evolving understanding of the relationship between the dosage form and its anatomical target, "biopharmaceutics" in the early 1960s. Since then it has been apparent that careful consideration of a molecule's physical chemical properties and those of its carrier, the dosage form, must be understood to enhance bioavailability, if given orally, and to enhance the ability of drug to reach the desired site of action, if given by other routes of administration. This knowledge allows for a rational stepwise approach in selecting new drug candidates, developing optimal dosage forms, and, later when it is necessary, making changes in the formulation or manufacturing processes. During the last decade or so, the basic approach of dosage-form development in the pharmaceutical industry has changed dramatically. Dosage-form design is now an "integrated process" starting from identification of drug molecules for development to their ultimate commercialization as dosage forms. This is often performed by a multidisciplinary team consisting of pharmacists, medicinal chemists, physical chemists, analytical chemists, material scientists, pharmacokineticists, chemical engineers, and other individuals from related disciplines.
In its simplest terms the dosage form is a carrier of the drug. It must further be reproducible, bioavailable, stable, readily scaleable, and elegant. The skill sets employed to design the first units of a dosage form, for example, a tablet, are quite different than those required to design a process to make hundreds of thousands of such units per hour, repro-ducibly, in ton quantities, almost anywhere in the world. Nevertheless, it is important that "design for manufacturability" considerations are made early although resource constraints and minimal bulk drug supply may not favor them. The manufacturability situation becomes understandably more complex as the dosage form becomes more sophisticated or if a drug-delivery system (DDS) is needed.
The level of sophistication in dosage-form design has been keeping pace with advances in discovery methods. New excipients, new materials, and combination products that consist of both a drug and a device have arisen to meet new delivery challenges. For example, many of the NCEs generated by high-throughput screening (HTS) are profoundly water-insoluble. What was considered a lower limit for adequate water solubility7 (~0.1 mg/mL) in the 1970s has been surpassed by at least an order of magnitude due to changes in the way drug discovery is performed. Traditional methods such as particle size reduction to improve the aqueous dissolution rate of these ever more insoluble molecules are not always sufficient to overcome the liability. New approaches have evolved to meet these challenges ranging from cosolvent systems8 to the use of lipid—water-dispersible excipi-ents9 and to the establishment of numerous companies with proprietary methods to increase bioavailability.
Many literature sources describing formulation and manufacture of different pharmaceutical dosage forms are available.10,11 The primary objective of this chapter is to describe an integrated process of drug development, demonstrating how all activities from lead selection to LCM are interrelated. Various scientific principles underlying these activities are described.
A survey of new drug approvals (NDAs) during the last 5 years (1999 to mid-2004) showed that nearly 50% of them are oral dosage forms. The percentage is higher if Abbreviated NDAs for generics are included. Therefore, the primary focus of this chapter is the development of oral dosage forms with a few other dosage forms described only briefly. However, many of the principles described in this chapter are common to all dosage forms.
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