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Questions and Answers
What does bioavailability measure?
What is the first indicator of drug solubility at GI pH?
Dissolution
What is the Noyes-Whitney equation primarily used to describe?
How does increased surface area affect drug dissolution?
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In vitro dissolution testing reflects ________ performance.
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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.
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Match the permeability assessment method with the description:
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Prodrugs are designed to decrease lipid solubility and absorption.
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Match the following terms with their description:
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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?
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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.
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Match the following dosage forms with their characteristics:
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What is absolute bioavailability?
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How is absolute bioavailability calculated?
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What is relative bioavailability?
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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?
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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.
