Druglikeness and BCS Overview

Druglikeness and the BCS

• Druglikeness and the Biopharmaceutics Classification System (BCS) are crucial for understanding and designing drugs.
• Drugs must have a delicate balance between hydrophilicity and lipophilicity to dissolve and act on their biological targets.
• Lipinski's Rule of Five: A drug should ideally obey at least two of these criteria to be orally absorbed:
  • Fewer than 5 hydrogen bond donors
  • Fewer than 10 hydrogen bond acceptors
  • Molecular weight less than 500 Da
  • LogP (octanol-water partition coefficient) less than 5.
• Limitations to Rule of Five: Doesn't account for drug absorption through transporters or drugs with very high/low aqueous solubility
• Additions to improve predictive power: Polar surface area less than 14 nm², lower limit for logP (i.e. excessive solubility), combined hydrogen bond donors and acceptors less than 12.

Learning Outcomes

• Describe physicochemical properties of a drug related to solubility and permeability.
• Define and apply the Rule of 5 to conventional small molecules.
• Define the Biopharmaceutics Classification System (BCS) and its four drug categories.
• Predict BCS solubility and permeability.
• Outline the uses of the BCS in pharmaceutical science.

Biopharmaceutics Classification System (BCS)

• The BCS is a classification system for orally administered drugs. It is based on two key metrics: solubility and permeability.
• Class I: High aqueous solubility and high permeability– Good liberation from dosage form and high passive permeation across lipid bilayers
• Class II: Low aqueous solubility and high permeability– Poor liberation from dosage form but high passive permeation across lipid bilayers
• Class III: High aqueous solubility and low permeability– Good liberation from dosage form but low passive permeation across lipid bilayers
• Class IV: Low aqueous solubility and low permeability– Poor liberation from dosage form and low passive permeation across lipid bilayers

Solubility in BCS

• High solubility: The highest dose strength dissolves in <250 mL of water over a pH range of 1-7.5 at 37°C.
• Solubility considerations should take into account dose, not just simple solubility metrics.

Permeability

• High permeability: The extent of absorption in humans is equal to or greater than 90%.
• Bioavailability testing– Involves healthy volunteers receiving a dose of the drug via IV and orally. Plasma levels are measured, and bioavailability is a ratio of absorbed via the tablet to bolus injected amount.
• In vitro permeability testing: Useful predictive method
• Caco-2 cells: Intestinal epithelial cells used for in vitro permeability estimations.

Biopharmaceutical Drug Disposition Classification System (BDDCS)

• Extends BCS by considering drug elimination, metabolism, distribution, and interactions.
• Used to predict lead behavior
• Outlines factors that govern drug ADME (absorption, distribution, metabolism, excretion)

Dissolution in BCS

• For Class I drugs, at least 85% of the dosage form must dissolve within 30 minutes in 900 mL of water at pH 1.2, 4.5, and 6.8 at 37°C.

Role of Charge (pKa)

• pKa plays a pivotal role in drug absorption, even though it's not explicitly part of BCS.
• Drug absorption for acids and bases is heavily affected by pH.

Applications of the BCS

• Generic drug approvals: The BCS helps determine if extensive bioequivalence trials are needed.
• Innovator drug characterization: BCS helps in characterizing drug solubility and permeability to help in formulation design
• Development classification system (DCS): Applying the concept further to product development efforts.

Other Important Considerations

• Permeability, solubility data, and logP are often correlated in evaluating drug behavior.

This quiz explores the concepts of druglikeness and the Biopharmaceutics Classification System (BCS), essential for drug design and development. Understand the criteria outlined in Lipinski's Rule of Five and its limitations, as well as additional factors that can improve predictive capabilities for drug absorption. Dive into the scientific principles that govern the solubility and permeability of drugs.