Medicines 1: Druglikeness and BCS Overview

Druglikeness and the BCS (I, II)

• The course covers Masters in Pharmacy (MPharm) and BSc Advanced Therapeutic Technologies
• The module is Medicines 1
• The lecturer is Dr Sam Maher

Learning Outcomes

• Describe the physicochemical properties of a drug important in solubility and permeability
• Define the Rule of 5 and apply it to conventional small molecules
• Define the BCS and the 4 drug categories
• Predict BCS solubility and permeability
• Outline the uses of BCS in pharmaceutical science

Drugs and Their Balance

• Drugs must dissolve to be absorbed and act on their biological target (e.g., receptors or enzymes)
• There's a delicate balance needed between hydrophilicity and lipophilicity

Lipinski's Rule of Five

• Hydrogen Bond Donors: Less than 5
• Hydrogen Bond Acceptors: Less than 10
• Molecular Weight: Less than 500 Da
• LogP (octanol-water partition coefficient): Less than 5
• A drug has to obey at least two of the parameters to be orally absorbed

Hydrogen Bond Donors and Acceptors

• Hydrogen bonding between a ketone and water (donor)
• Hydrogen bonding between a ketone and an amide (donor)

Limitations of Rule of 5

• Accounts for solubility, but not dissolution
• Doesn't account for drug absorption via transporters
• Accounts for low aqueous solubility, but not high

Additions to Improve Predictive Power

• Polar surface area (<14 nm²)
• Lower limit for LogP (ie. excessive solubility)
• Combined H-bond donor and acceptor of <12

Rule of 5 Case Drugs (examples)

• Aspirin: MW: 180.2, H-Donor: 1, H-Acceptor: 3, LogP: 1.19, Oral Bioavailability: 65-71%
• Glucose: MW: 180.2, H-Donor: 5, H-Acceptor: 6, LogP: -3.24, Oral Bioavailability: 100%
• Paracetamol: MW: 151.2, H-Donor:2, H-Acceptor: 2, LogP: 0.91, Oral Bioavailability: 62-89%
• Caffeine: MW: 194.2, H-Donor: 0, H-Acceptor: 3, LogP: -0.91, Oral Bioavailability: 100%
• Diazepam: MW: 284.7, H-Donor: 0 , H-Acceptor:3, LogP: 2.82, Oral Bioavailability: 85-100%
• Several other examples are given which include molecular weights, hydrogen donors, acceptors, logp and oral bioavailability percentages

Rule of 5: Other Examples

• Erythromycin: MW: 734, H-Donor: 14, H-Acceptor: 5, LogP: 2.6, Oral Bioavailability: 30-60%
• Alendronate: MW: 313.4, H-Donor: 8, H-Acceptor: 7, LogP: -2.77, Oral Bioavailability: 0.7%
• Desmopressin: MW: 1041, H-Donor: 17, H-Acceptor: 26, LogP: -3.72, Oral Bioavailability: 0.1%
• Ivermectin: MW: 875, H-Donor: 3, H-Acceptor: 14, LogP: 6.70, Oral Bioavailability: not determined

Biopharmaceutics Classification System (BCS)

• A scientific framework for classifying orally administered drugs based on solubility and permeability
• Breakdown into four classes based on different solubility and permeability properties

BCS Class I

• High aqueous solubility
• High permeability
• Good liberation from the dosage form
• High passive permeation across lipid bilayers

BCS Class II

• Low aqueous solubility
• High permeability
• Poor liberation from dosage form.
• High passive permeation across lipid bilayers, if the drug can be dissolved

BCS Class III

• High aqueous solubility
• Low permeability
• Good liberation from dosage form
• Low passive permeation across lipid bilayers

BCS Class IV

• Low aqueous solubility
• Low permeability
• Poor liberation from dosage form
• Low passive permeation across lipid bilayers

Solubility in BCS

• High solubility: The highest dose dissolves in < 250mL of water over a pH range of 1-7.5 at 37°C
• Take into account the dose when considering solubility, not just simple metrics. This now includes compendial solubility and the required dose in any measurements

BCS Solubility Examples

• Aspirin (high solubility): Relatively low solubility value but the highest dose is 300mg meaning 300mg/250mL (1.2mg/mL) makes aspirin high solubility
• Ibuprofen (low solubility): Low solubility value in absolute physical terms. The highest dose is 600mg meaning 600mg/250mL (2.4mg/mL), makes ibuprofen low solubility
• Digoxin (high solubility): Intermediate solubility value in absolute terms. However, the highest dose strength is 0.25 mg meaning 0.25mg/250mL which is high solubility

BCS Permeability

• High Permeability: Absorption is >90% in humans. Permeability can be tested by using bioavailability testing in humans or in vitro permeability tests
• Bioavailability (F): The fraction of a drug absorbed into the bloodstream, measured by comparing AUC (area under the curve) values in oral to intravenous administrations. The formula used is AUC_oral / Dose_oral ÷AUC_IV/Dose_IV
• In Vitro Measure of permeability: Intestinal cell cultures to predict fraction absorbed and bioavailability, and use of Apparent Permeability Coefficient (P_app), which gives a numerical measure of permeability

BCS Permeability Examples

• Various examples provided demonstrating how to calculate the bioavailability (F) of different drugs

Dissolution in BCS

• For BCS Class I, 85% of the dosage form must dissolve in 30 minutes at pH 1.2, 4.5, and 6.8 using USP Apparatus I or II at 37°C

Role of Charge (pKa)

• pKa plays a vital role in drug absorption, despite not being explicitly part of the BCS
• pKa is important to understand drug absorption, particularly for acids and bases

Applications of BCS

• Generic drug approval (aids the approval of generics after patent expiry)
• Waiving clinical trial requirement in certain cases (e.g., BCS Class I drugs)
• Characterization of drug candidates (used for classifying drugs to predict their behaviour for developing formulation strategies)

Develop ability classification system (DCS)

• Proposes using BCS as an oral drug development tool to aid in understanding the absorption limitations of drugs
• Categorizes BCS Class II drugs into dissolution-rate-limited and solubility-rate-limited drug types for target particle analysis
• Expands target particle size to include dissolution rate and solubility. Includes measurements in 500ml versus 250ml (BCS) and in specific acid volumes versus HCl (FSSIF)
• Aims to simplify the identification of absorption limitations in order to solve them

Other information

• Drug Disposition Classification System (BDDCS): extends BCS to include elimination, metabolism, distribution, potential for drug interactions, and predicts lead behaviour
• Several case studies are given showcasing BCS classification, parameters and drug properties

Explore the essential concepts of druglikeness and the Biopharmaceutical Classification System (BCS) in this quiz tailored for MPharm and BSc students. Learn about key physicochemical properties, Lipinski's Rule of Five, and the implications for drug absorption and efficacy. Test your understanding of these fundamental topics in pharmaceutical science.