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CHAPTER OBJECTIVES

  • Describe the biopharmaceutic factors affecting drug product design.

  • Define the term “rate-limiting step” and discuss how the rate-limiting step relates to the bioavailability of a drug.

  • Differentiate between the terms solubility and dissolution.

  • Differentiate between the concept of drug absorption and bioavailability.

  • Describe the various in vitro and in vivo tests commonly used to evaluate drug products.

  • Describe the methods for comparing two dissolution profiles for similarity.

  • List the compendial dissolution apparatus and provide examples of drug products for which these apparatus might be appropriate.

  • Define sink conditions and explain why dissolution medium must maintain sink conditions.

  • Define in vitro–in vivo correlation (IVIVC) and explain why a Level A correlation is the most important correlation for IVIVC.

  • Define clinically relevant drug product specifications and describe the methods to establish them.

  • Explain the biopharmaceutic classification system and how solubility, dissolution, and permeation apply to BCS classification.

  • Provide a description of some common oral drug products and explain how biopharmaceutic principles may be used to formulate a product that will extend the duration of activity of the active drug.

INTRODUCTION

Biopharmaceutics is the study of the physicochemical properties of both the drug substance and product and the in vitro quality attributes of the drug product as they relate to the bioavailability (BA) of the drug, with the goal of ensuring consistent drug product quality and the desired patient-centric therapeutic effect. BA refers to the rate and extent of appearance of active drug at the site of action. In practice, this is measured as the fraction of drug that reaches the systemic circulation.

Numerous routes of administration are available for drug products, such as ocular, nasal, pulmonary, transdermal, oral, rectal, vaginal, and parenteral (eg, intravenous, intra-arterial, intramuscular, intrathecal, subcutaneous). If the drug is given by an intravascular/intravenous (IV) route, systemic drug absorption is considered complete or 100% bioavailable, because the drug is placed directly into the general circulation. The choice of these routes is influenced by several factors which will be elaborated in this chapter. However, a salient consideration is the site of action for the drug to achieve its therapeutic objective. For systemically-acting drugs, the site of action is accessible via the systemic circulation and the drug must be absorbed to achieve a pharmacological response. Oral drug absorption involves the transport of the dissolved free drug through the gastrointestinal (GI) linings via passive and/or transporter-mediated pathways (Estudante et al, 2013). The passive route can be via a transcellular or paracellular mechanism depending on the hydrophilicity and size of the molecules (Lemmer and Hamman, 2013). The site of absorption along the GI tract depends, inter alia, on the drug substance properties and how the drug product is formulated, as discussed further in this chapter. For absorption to be feasible, drug release (or in vivo dissolution) from the drug product into the gut lumen’s fluids (juices) has to occur (with the exception ...

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