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Questions and Answers
What is one of the purposes of in vitro dissolution testing?
What is one of the purposes of in vitro dissolution testing?
Which of the following is NOT an application of performance assays?
Which of the following is NOT an application of performance assays?
Pharmacopeial standards serve what primary function in medicine?
Pharmacopeial standards serve what primary function in medicine?
Which parameter is crucial in determining the pharmacokinetics of oral dosage forms?
Which parameter is crucial in determining the pharmacokinetics of oral dosage forms?
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What aspect of performance testing could potentially change after scale-up of a drug?
What aspect of performance testing could potentially change after scale-up of a drug?
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How does high permeability of a drug influence its bioavailability?
How does high permeability of a drug influence its bioavailability?
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What is the main purpose of biopredictive test methods?
What is the main purpose of biopredictive test methods?
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In which scenario can bioequivalence be evaluated without a clinical trial?
In which scenario can bioequivalence be evaluated without a clinical trial?
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What factor can influence the non-dissolved fraction of a drug during dissolution testing?
What factor can influence the non-dissolved fraction of a drug during dissolution testing?
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What effect does food typically have on the dissolution of drugs?
What effect does food typically have on the dissolution of drugs?
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What two main parameters significantly influence the bioavailability of oral dosage forms?
What two main parameters significantly influence the bioavailability of oral dosage forms?
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How does drug formulation impact the absorption rate of a drug molecule?
How does drug formulation impact the absorption rate of a drug molecule?
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What role do clinical trials play in evaluating the permeability of compounds?
What role do clinical trials play in evaluating the permeability of compounds?
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Explain the significance of the Biopharmaceutical Classification System in drug development.
Explain the significance of the Biopharmaceutical Classification System in drug development.
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In what way does dose form influence the systematic circulation of a drug?
In what way does dose form influence the systematic circulation of a drug?
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Study Notes
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
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