Biopharmaceutics

Course Information

• Course code: PR5217
• Course title: Biopharmaceutics of Solid Oral Dosage Forms
• Instructor: Matthias G. Wacker, PhD
• Contact email: [email protected]
• Institution: National University of Singapore (NUS)

Learning Outcomes

• Understand the reasons for dissolution testing in solid oral dosage forms
• Learn the procedures, methods, and standards for dissolution testing of medicines
• Understand the challenges and applications of dissolution testing in drug development and testing

Biopharmaceutics

• The study of parameters influencing drug rate and amount reaching the site of action
• For many drugs, systemic circulation availability reflects target site availability
• Oral drug formulation characterization often includes solubility, permeability (BCS classification), dissolution testing, and in vitro-in vivo correlation

Absorption from the GI Tract

• The GI tract is composed of different compartments with varying residence times
• Passage times:
  • Esophagus: 10 seconds
  • Stomach: 0.1-5 hours
  • Small intestine: 1.5-2 hours
  • Colon: 1-24 hours

Noyes-Whitney

• Noyes and Whitney investigated factors influencing solid dissolution rate
• Dissolution rate depends on surface area, hydrodynamics, and concentration gradient
• Formula: dM/dt = DA(Cs - Cx)/h

Dissolution vs. Solubility

• Solubility limits the amount of monomolecular drug available in the GI tract
• Solubility ranges (mg/mL):
  • Freely soluble: 100-1000
  • Soluble: 33-100
  • Sparingly soluble: 10-33
  • Slightly soluble: 1-10
  • Very slightly soluble: 0.1-1
  • Practically insoluble: <0.1

Interindividual Differences

• Inter-individual differences in the human GI tract contribute to variability in clinical trials

GI Tract Anatomy

• Detailed anatomy of the GI tract is provided (with images) highlighting various cell types and compartments

pH of the Digestive Tract

• pH levels in various GI compartments:
  • Esophagus: ~6.8
  • Stomach: ~1.2
  • Small intestine (proximal): ~6.8
  • Small intestine (distal): ~6.8
  • Colon: ~6.8

Permeability

• Following FDA guidelines on permeability, determined based on human clinical trials or suitable in vitro/ex vivo/in vivo methods.
• Methods include:
  • Parallel Artificial Membrane Permeability Assay (PAMPA)
  • Caco-2 Cell Assay
  • Rat perfusion model

Influences of Dosage Forms

• Drug dissolution and dosage form together determine the rate and quantity of drug reaching the intestinal membrane
• Drug permeability determines the amount absorbed into systematic circulation

Biopharmaceutical Classification System (BCS)

• Solubility and permeability are key influence parameters
• Classification method that helps in estimating absorption

Summary

• Biopharmaceutics of oral dosage forms include the various processes affecting bioavailability
• Dissolution and permeability strongly influence oral absorption
• These criteria are major to evaluate performance
• Physiological factors (e.g., gastric emptying) may affect predictable processes

Performance Testing

Dissolution Testing

• Disintegration and dissolution are critical influences on drug pharmacokinetics
• In Vitro dissolution tests are relevant to predicting in vivo performance
• Dissolution tests assess lot-to-lot quality, guide formulation development, and ensure product quality

Applications of Dissolution Testing

• Routine quality control of drug batches
• Comparability testing after scaling up or post-approval changes (SUPACs)
• Assessing bioequivalence for biowaivers
• Discriminating between formulation candidates in development
• Predicting in vivo performance of drug products

Pharmacopeial Standards

• These standards set guidelines for drug quality testing
• The standards' evolution and applications are discussed

Dissolution Testing: Apparatus

• Various USP dissolution apparatus are described (Apparatus 1, 2, 3, and 4) with features and applications, including diagrams of apparatus
  • Apparatus 1 and 2 (Paddle- method for capsules)
  • Apparatus 3 (Reciprocating cylinder- mostly use for solid modified release dosage forms)
  • Apparatus 4 (Flow-through cell- Flexible medium composition, for solubility differences )

Dissolution Test

• Amount corresponding to single dose admin is measured
• Exact dimensions of the instruments outlined in pharmacopeia
• Temperature kept constant at 37°C ± 0.5°C
• Kinetic measurement of release/dissolution

Deaeration

• Insufficient deareation can significantly limit reproducibility
• The air-liquid interface creates additional shear stress, reducing surface area available for dissolution

Sink Conditions

• Dissolution rate is measured accurately only if the drug does not reach its solubility limit immediately
• Introduced to account enable accurate discrimination by rate rather than solubility differences
• Solubility in the dissolution vessel must be significantly higher than the needed amount

Typical QC Dissolution Test (Highly Soluble Drugs)

• Simulated intestinal fluid (pH 6.8)
• 500 mL medium, 37°C, & 75 rpm
• Testing times are 7.5, 15, 30, 60, and 90 minutes

Quality Control Specs

• One-point specification for immediate release (IR) forms (about 80 percent within 45 min)
• Three-point specification is used for modified release (MR) forms (about 20-30%, 50%, and 80 percent

Biowaiver

• Products with similar pharmacokinetic profiles can be considered equally bioavailable
• If the drug is highly permeable, bioavailability mainly depends on dissolution rate
• In vitro testing can be used in place of in vivo clinical trails when applying biowaiver

Biopredictive Testing

• Predictive testing methods mimic GI tract conditions (e.g., simulated fluids) to forecast pharmacokinetics

Methods: GI tract Schematic

• Diagram illustrating the release and transportation processes, including the stomach, intestines, colon etc.

Dissolution Experiment and Gastric Emptying Model

• Diagrams demonstrating in vitro dissolution testing of the tablet, highlighting the stages and parameters that affect the process
• Diagrams describing gastric emptying models simulating dissolution processes.

Food Effects (Pediatric Breakfast)

• Diagrams and data tables showing the effect of pediatric breakfast on the dissolution of two drugs, highlighting how the choice of food affects the dissolution process

Mimicking Physiology In Vitro (Diagram)

• Diagram of a complex apparatus for replicating physiological conditions to test the solubility process of a given reagent/material under simulated GI conditions

Summary (Final)

• Biopharmaceutical characterization facilitates drug delivery
• Performance testing uses strict standards
• Specifications vary depending on the drug type
• Biowaivers offer an in vitro alternative to clinical testing for generic approvals
• Biopredictive testing more closely mimics physiology to predict pharmacokinetics