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Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. Different models have been established for the parallel screening of these biopharmaceutical properties, including membrane-based models (PAMPA), cell culture-based models (such as Caco-2 and MDCK cell lines), and the Ussing chambers technique. In this chapter, the strengths and the drawbacks of these models are discussed, while examples of applications for these different models and suggestions to improve the models are provided. Finally, different in vitro methods for studying the intestinal metabolism are also described. As the intestinal absorption process depends on a multitude of parameters, a single universal model accounting for all these parameters does not exist. Therefore, combination of different in vitro models should be considered in order to obtain better insights in intestinal drug absorption in the different phases of drug discovery and development. [ABSTRACT FROM AUTHOR]

Formulation of proteins and peptides has been primarily achieved through aqueous solutions or lyophilized cakes for reconstitution. Therefore, the incorporation of non-aqueous formulation techniques has been limited by the lack of general applicability. However, the advent of biotechnology, bioengineering and pharmaceutical delivery systems has increased the requirements for drug solubility and stability under a variety of conditions, and required scientists to pursue alternative strategies. For example, the exploration of drug delivery systems for macromolecules and novel applications for enzyme chemistry have driven the usage of alternate solvent systems. [ABSTRACT FROM AUTHOR]

This chapter focuses on solubilizing excipients in oral formulations with selected examples of commercially available over-the-counter and prescription human pharmaceutical products. The intent is to educate the reader on the need for and the chemical contents of solubilized oral formulations, and to act as a practical guide in assisting the development scientist in choosing a solubilizing vehicle for oral administration. The formulation philosophy is to minimize the excipients and the suggested development approach is from "simple to complex" (i.e., keep the formulation as simple as possible). This chapter is organized in four sections. The first section is an introduction with basic concepts. The second section addresses solubilizing excipients and mixtures of excipients. The third section deals with liquid-filled capsules. The fourth section focuses on oral solutions. The last three sections are further divided into water-soluble vehicles and lipidcontaining vehicles. [ABSTRACT FROM AUTHOR]

It must first be recognized that formulating compounds and delivering them as aerosols is complex. Not only does it involve the formulation of a stable solution or suspension in a medium (propellant) that is not as well characterized as other systems, but the resultant system is also subject to performance limitations. In order to efficiently reach the lung, the formulation must be atomized into particles having aerodynamic sizes between approximately 1 and 5 microns. Due to these particle size constraints, as well as inhalation toxicology concerns, the range of possible excipients to choose from during the formulation phase is substantially reduced. Additionally, limiting the concentration of excipients in a formulation is crucial for maintaining adequate aerosol performance. Thus, given the complexity of this relationship, formulating aerosols is a challenging endeavor. [ABSTRACT FROM AUTHOR]

The selection of a vehicle can dramatically affect delivery and consequently efficacy of topical preparations. In terms of transdermal delivery, where delivering therapeutic agents for systemic effects is desired, solvents and co-solvent systems are widely used to improve both the amount and range of drugs that can be administered at therapeutic levels through the skin. Vehicles used in transdermal systems, such as patches, have recently been reviewed (Williams, 2003). In contrast, the focus of this chapter is on the use of solvents in topical dosage forms, i.e. preparations intended for a local or regional effect on the skin. [ABSTRACT FROM AUTHOR]

Protein solubility ranges from low micrograms per ml to several hundreds of milligrams per ml, and is very compound-specific. Most antibodies are known to reach solubilities of hundreds of mg per ml whereas beta amyloid protein has very low solubility. Small structural changes could lead to significant changes in solubility, for example, cryo-immunoglobulins may be almost insoluble. The dose and route of administration may demand a higher concentration than possible in simple formulations, posing a challenge to the development of a clinically or commercially viable product. One important challenge is that proteins are typically administered via injections due to poor bioavailability by other delivery modes (See review articles in book edited by Audus and Raub, 1993; Pharmaceutical Business Review website, 2005), which restricts the types and levels of excipients (FDA website; Powell et al., 1998; Strickley, 1999, 2000). Further constraints are imparted by the small volume of administration appropriate for subcutaneous and intramuscular delivery routes which need to be consistent with patient compliance and ease of delivery. This can be very different from the volume/ concentration constraints of intravenous administration. For therapeutic doses in the mg/kg levels, the less than approximately 1.2 mL acceptable volume for subcutaneous delivery may necessitate formulations containing hundreds of mg/mL protein. Moreover, toxicological studies may assess approximately 10- fold higher doses than those planned for clinical studies in order to establish a safety window. This necessitates even higher concentrations for non-clinical formulations than for clinical formulations. [ABSTRACT FROM AUTHOR]

"Parenteral" is defined1 as "situated or occurring outside the intestine, and especially introduced otherwise than by way of the intestines"—pertaining to essentially any administration route other than enteral. This field is obviously too broad for an adequate focus in one book, let alone one chapter. Many have nonetheless used the term synonymously with injectable drug delivery. We restrict ourselves to this latter usage. This would thus include intravenous, intramuscular, subcutaneous, intrathecal, and subdural injection. In this chapter we discuss the theoretical and practical aspects of solubilizing small molecules for injectable formulation development and will examine the role of surfactants and other excipients in more recent parenteral delivery systems such as liposomes, solid-drug nanoparticles and particulate carriers. [ABSTRACT FROM AUTHOR]

The purpose of this chapter is two-fold and includes approaches for identifying potentially problematic drug candidates with regard to formulation, in general, and for the preparation of toxicology vehicles, in particular. In addition, an attempt is made to provide insight as to what oral and parenteral excipients are appropriate for early human testing and, by extension, which of these materials can reasonably be used in GLP toxicology evaluation intended to support these Phase I human assessments. These considerations are becoming more visible in the drug development arena as evidenced by a number of recent symposia and congresses (Liu 2005; Van Gelder, 2006). [ABSTRACT FROM AUTHOR]

Oral administration is the most convenient way to deliver drugs, and therefore the most preferred. However, the oral route is very complex based on the physiological conditions encountered by the drug as it passes from the mouth to the absorptive sites in the intestine. When moving from the stomach through the pylorus into the small intestine, the drug will meet a rapidly changing environment including bile and pancreatic secretions which will introduce different enzymes and surface active bile components, and increase in pH from acidic to neutral. Physiological factors such as the rate of gastric emptying, intestinal motility, blood flow, as well as volume, composition and pH of alimentary secretions are known to impact the rate and/or extent of drug absorption. The basic parameters determining the absorption of a drug compound after oral administration are its solubility and permeability in the conditions associated with the gastrointestinal (GI) tract. [ABSTRACT FROM AUTHOR]

In the past, drug discovery was mainly linearly oriented: discovery compounds were primarily synthesized in view of optimizing their pharmacological activity, often resulting in poorly water-soluble and highly lipophilic compounds. In contrast to the traditional discovery paradigm, drug discovery today is more and more practiced in parallel design, where the pharmacological potency is screened concurrently with the initial ADMET profiling of compounds. For a compound to be a successful drug, it should not only have pharmacological activity, but also adequate biopharmaceutical properties enabling it to reach the site of action. This approach permits one to improve the quality of generated drug candidates, to have greater probability of success in the clinic and to guide the chemists in the selection of compounds with better biopharmaceutical properties. [ABSTRACT FROM AUTHOR]

Solubility is one of the most important physicochemical properties studied during pharmaceutical preformulation. For liquid dosage form development, accurate solubility data are essential to ensure the robustness of the finished product. For solid dosage forms, solubility data are important in determining if an adequate amount of drug is available for absorption in vivo. If a compound has a low aqueous solubility, it may be subject to dissolution rate-limited or solubility-limited absorption within the gastrointestinal (GI) residence time (Lobenberg et al., 2000). The importance of solubility, in biopharmaceutical terms, is highlighted by its use in the biopharmaceutics classification system (BCS) described by Amidon et al. (1995). This system defines low solubility compounds as those whose aqueous solubility in 250 mL of pH 1-7.5 aqueous solution is less than the total dose. Solubility data are also used to estimate the maximum absorbable dose (MAD) (Johnson and Swindell, 1996). MAD is a conceptual tool that relates the solubility requirement for oral absorption to the dose, permeability and GI volume and transit time. It is defined as: [ABSTRACT FROM AUTHOR]

Drug discovery programs begin with target identification and validation for diseases with unmet medical needs (Figure 1). Drug discovery targets that are currently available mostly fall into two categories, with 45% being receptors and 28% being enzymes (Table 1) (Drews, 2000). There are only 483 targets addressed by all drugs in the pharmaceutical industry, which is a relatively small number compared to the estimated 3000-10,000 disease relevant genes (Meisner et al., 2004). It is evident that the drug target universe is far from being fully exploited. [ABSTRACT FROM AUTHOR]

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodríguez-Hornedo and Murphy, 1999; Shekunov and York, 2000; Rodríguez- Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purification during the intermediate and final stages of drug synthesis. Moreover, solution crystallization determines the final solid-state modification of the API namely polymorphs, solvates, and hydrates. [ABSTRACT FROM AUTHOR]

Many drug substances can be classified as being either acids or bases in that they possess the ability to react with other acids or bases that are stronger than themselves. As such, they would also possess the ability to exist as ionic species under certain conditions. The state of ionization of a substance will often profoundly affect its degree of aqueous solubility, as evidenced by the high solubility of sodium benzoate as opposed to the low solubility of benzoic acid. The utility of salt forms as active pharmaceutical ingredients is well known, and represents one of the means to increase the degree of solubility of an otherwise intractable substance (Berge et al. 1977; Stahl and Wermuth 2002). [ABSTRACT FROM AUTHOR]

Solubility is defined as the maximum quantity of a substance that can be completely dissolved in a given amount of solvent, and represents a fundamental concept in fields of research such as chemistry, physics, food science, pharmaceutical, and biological sciences. The solubility of a substance becomes especially important in the pharmaceutical field because it often represents a major factor that controls the bioavailability of a drug substance. Moreover, solubility and solubility-related properties can also provide important information regarding the structure of drug substances, and in their range of possible intermolecular interactions. For these reasons, a comprehensive knowledge of solubility phenomena permits pharmaceutical scientists to develop an optimal understanding of a drug substance, to determine the ultimate form of the drug substance, and to yield information essential to the development and processing of its dosage forms. [ABSTRACT FROM AUTHOR]