Podcast
Questions and Answers
What does bioavailability measure?
What does bioavailability measure?
What is the first indicator of drug solubility at GI pH?
What is the first indicator of drug solubility at GI pH?
Dissolution
What is the Noyes-Whitney equation primarily used to describe?
What is the Noyes-Whitney equation primarily used to describe?
How does increased surface area affect drug dissolution?
How does increased surface area affect drug dissolution?
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In vitro dissolution testing reflects ________ performance.
In vitro dissolution testing reflects ________ performance.
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The stability of a drug in gastrointestinal fluids does not affect its bioavailability.
The stability of a drug in gastrointestinal fluids does not affect its bioavailability.
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Drug solubility in the diffusion layer is a critical factor for the determination of ________ rate.
Drug solubility in the diffusion layer is a critical factor for the determination of ________ rate.
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Match the permeability assessment method with the description:
Match the permeability assessment method with the description:
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Prodrugs are designed to decrease lipid solubility and absorption.
Prodrugs are designed to decrease lipid solubility and absorption.
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Match the following terms with their description:
Match the following terms with their description:
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What is the function of co-solvents in drug delivery?
What is the function of co-solvents in drug delivery?
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Which type of molecules are trapped inside cyclodextrins to increase aqueous solubility?
Which type of molecules are trapped inside cyclodextrins to increase aqueous solubility?
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Micellar solubilization helps to improve the solubility of drugs, leading to an increase in ________.
Micellar solubilization helps to improve the solubility of drugs, leading to an increase in ________.
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Higher hydrogen bonding leads to increased drug absorption.
Higher hydrogen bonding leads to increased drug absorption.
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Match the following dosage forms with their characteristics:
Match the following dosage forms with their characteristics:
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What is absolute bioavailability?
What is absolute bioavailability?
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How is absolute bioavailability calculated?
How is absolute bioavailability calculated?
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What is relative bioavailability?
What is relative bioavailability?
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How is relative bioavailability calculated?
How is relative bioavailability calculated?
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Which curve is used for assessing bioavailability when looking at cumulative excreted drug or metabolites over time?
Which curve is used for assessing bioavailability when looking at cumulative excreted drug or metabolites over time?
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Study Notes
Factors Affecting Absorption and Bioavailability of Drugs
- Physiological factors, physicochemical factors, dosage form, and formulation factors can affect drug absorption and bioavailability.
- Physiological factors include:
- Gastric emptying rate
- GI motility
- Blood flow
- Enzyme activity
- pH at the absorption site
- Physicochemical factors include:
- Solubility
- Dissolution rate
- Particle size
- Surface area
- Wettability
- Ionization
- Lipid solubility
- Crystal form
- Dosage form factors include:
- Type of dosage form (solution, suspension, or solid)
- Manufacturing method
- Excipients used
- Particle size and distribution
Mechanism and Noyes-Whitney Equation
- Dissolution is the transfer of solute into solution
- Dissolution process is described by the Noyes-Whitney equation: dm/dt = (DAΔC) / h, where ΔC = Cs - C
- The Noyes-Whitney equation relates the dissolution rate to the concentration difference between the saturated solution and the bulk solution
Physiological Factors
- Gastric emptying rate can affect drug absorption
- GI motility can affect drug absorption
- Blood flow can affect drug absorption
- Enzyme activity can affect drug absorption
- pH at the absorption site can affect drug absorption
Physicochemical Factors
- Solubility is a critical factor for drug absorption
- Dissolution rate can affect drug absorption
- Particle size and surface area can affect drug absorption
- Wettability can affect drug absorption
- Ionization can affect drug absorption
- Lipid solubility can affect drug absorption
- Crystal form can affect drug absorption
Drug Factors
- Surface area can affect drug absorption
- Wettability can affect drug absorption
- Solubility in the diffusion layer can affect drug absorption
- Extent of ionization can affect drug absorption
- Crystal form can affect drug absorption
- Drug concentration in the bulk of GI fluids can affect drug absorption
Complexation
- Complexation can be beneficial or detrimental to drug absorption
- Examples of complexation include:
- Streptomycin and mucin
- Tetracyclines and calcium
- Bisphosphonates and food
Micellar Solubilization
- Micellar solubilization can increase drug solubility
- Examples of micellar solubilization include:
- Bile salts and lipophilic drugs
Adsorption of Drugs
- Adsorption of drugs can affect drug absorption
- Examples of adsorption of drugs include:
- Concurrent drug administration
- Activated charcoal and promazine
- Glidant and cyanocobalamin
Chemical Stability in GI Fluids
- Chemical stability in GI fluids is essential for drug absorption
- Examples of chemical stability in GI fluids include:
- Acidic and enzymatic hydrolysis
- Gastro-resistant formulations
Prodrugs
- Prodrugs can increase lipid solubility and absorption
- Examples of prodrugs include:
- Pivampicillin (Ampicillin + Pivaloyloxymethyl)
- Cefuroxime axetil (Cefuroxime + Acetylethyl)
Improving Bioavailability of Poorly Soluble Drugs
- Methods to improve bioavailability of poorly soluble drugs include:
- Salt formation
- Cosolvents
- SDDS (self-emulsifying drug delivery systems)
- Micellar solubilization
- Cyclodextrins
- SEDDS (self-emulsifying drug delivery systems)
- Permeation enhancers
Improving Bioavailability of Poorly Soluble Drugs due to Lipophilicity
- Methods to improve bioavailability of poorly soluble drugs due to lipophilicity include:
- Cosolvents
- SDDS (self-emulsifying drug delivery systems)
- Micellar solubilization
- Cyclodextrins
- SEDDS (self-emulsifying drug delivery systems)
- Permeation enhancers
Improving Bioavailability of Drugs with Poor Permeability
- Methods to improve bioavailability of drugs with poor permeability include:
- Permeation enhancers
- Molecular size and hydrogen bonding
- Enzyme inhibition
Permeation Enhancers
- Permeation enhancers can increase drug absorption
- Examples of permeation enhancers include:
- Surfactants
- Bile salts
- Medium chain fatty acids
- Chelating agents
- FaHy acids and bile salts
Molecular Size and Hydrogen Bonding
- Molecular size and hydrogen bonding can affect drug absorption
- Examples of molecular size and hydrogen bonding include:
- Paracellular absorption
- Transcellular passive diffusion### Factors Affecting Bioavailability
- Aqueous suspension leads to a non-precipitating aqueous solution, ultimately achieving a condition of aqueous suspension
- Drug in a hard gelatin capsule or tablet ultimately achieves a condition of aqueous suspension
- Factors associated with aqueous suspension affect bioavailability, including:
- Particle size
- Crystal form
- Complexation
- Inclusion of surfactants
- Viscosity of formulation
Liquid-Filled Capsules
- Liquid-filled capsules contain SoA or hard gelatin/HPMC
- Drug inside the capsule is dissolved or dispersed in a non-toxic, non-aqueous vehicle
- Water miscible vehicle: content of the capsule is released, vehicle disperses/dissolves, and the drug is released as a solution/suspension
- Water immiscible vehicle: content of the capsule is released, facilitated by dispersing agents, and the drug is released as a solution/suspension/emulsion/micro-emulsion
- Lipophilic vehicle: digested oil, drug is highly soluble in the vehicle, and fat absorption process occurs
Powder-Filled Capsules
- Bioavailability from a powder-filled capsule is similar to compacted tablets, provided factors are controlled
- Rate of drug dissolution from the capsule is a complex function of different processes
- Excipients in the capsule dosage form influence the rate of dissolution
- No adsorption of the drug by excipients
- Factors associated with the making of powder-filled capsules affect bioavailability, including:
- Surface area and particle size
- Use of salt form of the drug
- Crystal form
- Stability of the drug
- Drug-excipient interaction
- Nature and quantity of excipients
- Type and condition of the filling process
- Packing density
- Composition and properties of the capsule shell
- Interaction between the capsule shell and its content
Tablets (Uncoated)
- Tablets reduce the surface area, and excipients are added to bring the drug into a pre-compacted state
- Poorly soluble drug: rapid disintegration and release, fine and well-dispersed suspension in GI fluids, and dissolution and absorption
- Disintegration is affected by the concentration and type of drug, excipients, and compaction pressure
- Dissolution of poorly soluble drug in the tablet is comparable to the dissolution of the drug in a fine, well-dispersed suspension
- Factors associated with the making of uncoated tablets affect bioavailability, including:
- Physico-chemical properties of the drug
- Nature and quantity of excipients
- Drug-excipient interaction
- Size and method of making granules
- Compaction pressure and compaction speed
- Storage condition and age of the tablet
Tablets (Coated)
- Coating application on tablets possesses bioavailability-related problems (uncoated tablets) and additional problems related to the physico-chemical nature and thickness of the coating
- Sugar-coated tablets: sealing the coat (Shellac and CAP) and annealing agents (PEGs, CaCO3) added to reduce water impermeability
- Film-coated tablets: HPMC, soluble at GI pH, and acrylic resins or EC, hydrophobic, reduce drug release
- Gastro-resistant tablets: CAP, HPMC Phthalate, copolymers of methacrylic acid and their esters, and Polyvinyl acetate Phthalate, dissolve at pH 5
- Gastro-resistant coatings offer delayed onset of action
Influence of Excipients
- Excipients are added to facilitate preparation, patient acceptability, and functioning of the dosage form as a drug delivery system
- Excipients interact with the active drug, having the potential to influence the release, absorption, and other characteristics of the drug
- Examples of excipients: diluents, surfactants, lubricants, disintegrants, viscosity enhancers, binders, lubricants, colorants, stabilizers, flavoring agents, suspending agents, emulsifiers, etc.
Biopharmaceutical Characteristics
- Biopharmaceutical characteristics are factors affecting the rate and extent of drug absorption
- Key biopharmaceutical properties: release of the drug, stability, ability to cross and pre-systemic metabolism
- Bioavailability is the overall measurement of the availability of the drug in systemic circulation
Assessment of Bioavailability
- Release of drug: dosage form design controls the release of the drug
- Solubility of the drug at GI pH is the first indicator of dissolution
- Rate of dissolution is determined by intrinsic and dosage form properties
- In vitro dissolution testing reflects in vivo dissolution performance
- Scientists focus on in vitro–in vivo correlations, which are useful for drugs where dissolution is rate-limiting
- In vitro dissolution testing is used to study the dissolution profile of the drug in various physiological media
Partition Coefficient
- Partition coefficient of the molecule is determined between oil and water phases (log P)
- Log P is a measure of the lipophilicity of the molecule
- Shake flask method is commonly used
- Aqueous phase is saturated with oily phase and vice versa
- Constant temperature is maintained, and the drug is added and allowed to reach equilibrium
- Distribution coefficient (log D) is determined, which is useful for weakly acidic or basic drugs
Cell Culture Techniques
- Cell culture techniques are widely used to predict intestinal absorption
- Caco-2 cell line is used to mimic cells in the small intestine
Perfusion Studies
- Rat model is preferred for perfusion studies due to ease of use and similarity to human intestinal permeability
- In situ intestinal model is used, and the whole animal is used
Pre-systemic Metabolism
- Intestinal cell fractions (brush border membrane preparations) are used to study pre-systemic metabolism
- Various liver preparations are used to study phase I and phase II metabolism reactions
Plasma Concentration-Time Curve
- Plasma concentration-time curve is used to assess bioavailability
- Three different formulations A, B, and C are administered to the same person at different times
- Same route of administration is used
- Assumptions: sufficient time has elapsed between the administration of each formulation, and no residual concentration and residual effects
- Kineics and pattern of distribution, binding phenomenon, and experimental conditions are all the same
Urinary Excretion Curve
- Urinary excretion curve is used to assess bioavailability
- Intact drug and/or metabolites are assayed in the urine
- Assumptions: no drug metabolism before reaching systemic circulation
- Urinary excretion studies are used to construct a cumulative urinary excretion curve
- Urine samples are collected until all the drug and/or metabolites are excreted
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Description
This quiz covers the factors affecting absorption and bioavailability of drugs, including physiological, physicochemical, dosage form, and formulation factors. Understand the role of each factor in drug delivery.
