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An API's therapeutic effectiveness depends on its bioavailability and, ultimately, on its solubility. If an API is poorly water soluble, then it cannot get into solution. If it is not in solution, it cannot be absorbed by the body. In fact, poor aqueous solubility leads to inadequate and variable absorption via the GI tract and that diminishes efficacy. Optimizing an API's solubility and bioavailability is one of the top challenges for formulators in the pharmaceutical and biotech industries. Furthermore, overcoming the chal- lenge almost always increases development costs, lengthens development timelines, and raises the potential for delays in regulatory approval. Poorly water-soluble or hydrophobic new chemical enti- ties (NCEs) have dominated drug discovery programs for years. According to some estimates, nearly half of the drug products currently on the market have shown aqueous solu- bility issues. Additionally, a large number of the NCEs in early development show poor aqueous solubility. Assessing bioavailablity The Biopharmaceutics Classification System (BCS) was developed to help characterize solubility and permeability issues. It divides APIs into four categories, or classes. Class 1 APIs demonstrate high solubility and high permeability. Class 2 APIs have low solubility and high permeability. Class 3 APIs have high solubility and low permeability. Class 4 APIs exhibit both low solubility and low permeabil- ity (Figure 1). In general, API absorption, bioavailability, and the pharmacokinetic profile of an orally administered API is highly dependent on the solubility of that compound in an aqueous medium. When an API is given orally, it must first dissolve in gas- tric and/or intestinal fluids before it can permeate the mem- branes of the GI tract to reach systemic circulation. An API with poor aqueous solubility will typically exhibit "dissolu- tion-rate-limited" absorption, while an API with poor mem- brane permeability will typically exhibit "permeation-rate- limited" absorption. Bioavailability is a subcategory of absorption and repre- sents the fraction of an administered dose of unchanged API that reaches systemic circulation. It is one of the princi- pal pharmacokinetic properties of a drug product. Factors that affect bioavailability include the API's chemical and physical properties (e.g., solubility, particle size, physical form—crystalline or amorphous), stability, the drug prod- uct's formulation (immediate release versus extended or some type of modified release), the excipients the product includes, and how the product is manufactured. Bioavailability may also be affected by gastric empting rate, i.e., insufficient time for absorption and the health of the GI tract, which may be affected by age, stress, surgery, metabolism differences, metabolism by luminal microflora, and/or fed versus fasted state. Poorly soluble APIs often require high doses in order to reach a therapeutic effect after oral administration. This can 30 July 2016 Tablets & Capsules Figure 1 The Biopharmaceutics Classification System for APIs Class 1 Class 2 Class 3 Class 4 High solubility High permeability Low solubility High permeability High solubility Low permeability Low solubility Low permeability Chemical considerations Permeability Formulation considerations Solubility Formulation considerations