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24 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com Formul ation and drug delivery drugs are metabolized and inactivated in the liver by cytochrome P450 enzymes. The metab- olism process varies by patient and is affected by genetics, age, and interactions with other drugs. • Excretion: By this process, drugs and their me- tabolites are removed from the body. If excretion is incomplete, drug substances can accumulate to problematic levels. The kidneys are the most common route for excretion, and their perfor- mance can be affected by age, renal function, and pathologies that affect renal blood flow. Predicting and controlling the pharmacokinetic properties of a substance presents a major challenge for drug delivery innovators. To help with this chal- lenge, the Biopharmaceutics Classification System (BCS) has been developed as a prognostic tool for as- sessing the absorption parameter of drugs using quan- titative data on water solubility and membrane perme- ability. Drug formulators can use this to predict the rate-limiting step in the intestinal absorption process that follows oral administration. A drug substance is considered soluble when the highest clinical dose can be dissolved in 250 mL or less of an aqueous me- dium under specific pH and temperature conditions. A substance is highly permeable when 90% of an ad- ministered dose is absorbed. New chemical entities (NCEs) can be characterized as belonging to Class I-IV according to these properties, as shown in Figure 2 (13). Because of its lower cost, simplicity, convenience, and patient compliance, ora l administration is a strongly preferred dosage form. However, NCEs are being increasingly categorized as poorly soluble (Class II), poorly permeable (Class III), or both (Class IV), and this dramatically increases the probability that they will need to be delivered in non-oral form. As a result of these recent trends, developers are working to shift Class II-IV substances toward Class I by increasing solubility, decreasing particle size, and incorporating permeation enhancers. TPGS as a surfactant The hydrophilic nature of polyethylene glycol and the lipophilic phytyl chain of d-α-tocopherol confer amphiphilic properties on the TPGS molecule and allow it to self-assemble in water when concentrations exceed the threshold known as the critical micelle FIGURE 3. Pathways for intestinal drug absorption.