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Questions and Answers
What are the two parameters that govern drug absorption in the BCS classification?
Why is dissolution testing significant in drug product development?
What is the difference between absolute bioavailability and relative bioavailability?
Which factors affect drug absorption and bioavailability?
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What is a characteristic feature of USP dissolution studies?
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What is the percentage of bioavailability for drugs administered via the intravenous route?
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What must occur for any drug administered via routes other than intravenous to enter the bloodstream?
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Which of the following best describes absolute bioavailability?
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If a drug administered orally has a bioavailability of 80%, what does this indicate?
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What does an increase in absorption imply regarding drug bioavailability?
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What is required by the U.S. FDA to control the quality of pharmaceutical products?
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Which of the following parameters is NOT specified in the USP drug monographs for dissolution analysis?
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What is the significance of measuring the time for 75% of the labeled amount of drug to dissolve according to USP guidelines?
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What type of apparatus uses a rotating basket during the dissolution testing process?
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Which class of drugs typically has low solubility and low permeability?
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What mechanism do most drugs use to permeate biological membranes?
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What condition must the dissolution medium be kept at during testing?
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What role does a drug's ability to partition into a lipophilic membrane environment play?
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What is a key characteristic of facilitated diffusion?
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How does active transport differ from facilitated diffusion?
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What is the role of the Caco-2 monolayer in studying drug permeation?
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Which statement is true regarding the factors affecting oral bioavailability?
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What indicates successful formation of a Caco-2 monolayer?
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Which concept describes the competitive inhibition related to membrane transporters?
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During active transport, which of the following is necessary?
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What happens when the integrity of the Caco-2 monolayer is compromised?
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What is the maximum number of hydrogen-bond donors according to Lipinski's Rule of Five for good oral absorption?
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Which of the following factors does not predict a compound's pharmacological activity according to Lipinski's Rule of Five?
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What role do excipients play in drug absorption?
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According to Lipinski's Rule of Five, what is the limit for hydrogen-bond acceptors?
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What is the maximum molecular weight suggested by Lipinski's Rule of Five to ensure good oral absorption?
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Which of the following does NOT represent a common type of drug based on the content?
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What is one key purpose of dissolution testing in drug product development?
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Which of the following describes a scenario where excipients could modify drug absorption?
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What is a key concern when using sustained release formulations in relation to alcohol intake?
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What technology is employed in Meltrex Technology for controlled release formulations?
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What primary disadvantage is associated with matrix devices in drug release?
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Which statement about the Meltrex Technology is true?
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In the context of drug release, what is essential to achieve zero order release from matrix devices?
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What is a potential consequence of breaching the release control barrier in sustained release formulations?
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What is the main method of drug absorption that requires no energy?
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Which of the following best describes the scalability of Meltrex Technology?
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What is the main factor that determines the release rate of drug molecules in a diffusion-controlled release formulation?
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Which parameter is NOT necessary to maintain for a constant drug release rate from a reservoir device?
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What role does the polymer material play in a reservoir diffusion system?
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Which of the following factors does NOT affect the release rate of a drug from a reservoir device?
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What equation describes the release rate of a drug from a diffusion-controlled release formulation?
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In a matrix diffusion system, what primarily influences drug release?
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What is one reason why a combination of dissolution and diffusion may occur in microencapsulated material?
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How is the partition coefficient significant in the context of diffusion-controlled release formulations?
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What is the primary function of cholestyramine in pharmaceuticals?
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Which statement accurately describes the action of osmotic controlled delivery systems?
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What determines the volume flow of water into the core of an osmotic system?
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Which of the following is a cation exchange resin mentioned?
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What factor is crucial to ensuring that the hydrostatic pressure difference is minimized in an osmotic system?
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What is colestipol primarily used for?
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Which property is associated with osmotic delivery systems?
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What parameter is NOT included in the equation for volume flow of water into the core of an osmotic system?
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What is the primary function of the push layer in the trilayer core of Concerta®?
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Which statement accurately describes the initial release of methylphenidate in Concerta®?
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What is a benefit of gastroretentive drug delivery systems?
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Which type of drug is most appropriate for use in gastroretentive drug delivery systems?
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What characteristic is essential for the orifice of Concerta® to function properly?
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How does the average gastrointestinal transit time impact drug release from gastroretentive systems?
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Why are certain drugs selected for gastroretentive delivery systems?
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What role does water play in the drug release mechanism of Concerta®?
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Which type of gastroretentive system uses polymers that adhere to the stomach lining?
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Which mechanism is least effective in increasing gastric residence time for drugs?
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What is a key characteristic of size increasing gastroretentive systems?
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Which of the following substances is NOT suitable for gastroretentive DDS?
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How do effervescent floating systems maintain their position in the stomach?
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Which of the following describes an appropriate action to avoid premature emptying of a gastroretentive dosage form?
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What is one of the components used in an effervescent floating system?
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Which characteristic of a gastric retentive system enhances its ability to be cleared from the stomach after multiple uses?
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What is the primary advantage of using microencapsulation for drug delivery?
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In the Noyes-Whitney equation, what does 'D' represent?
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Which factor can be varied to control the rate of drug release in coated granules?
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What is one key characteristic of microencapsulated particles?
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How does the composition of the coating material impact drug release?
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Which method utilizes oppositely charged aerosols for microencapsulation?
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What characteristic of a tablet matrix primarily controls the rate of drug dissolution?
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Which coating material is suitable for interfacial polymerization in microencapsulation?
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Which method can be used to control drug release by manipulating the effective porosity of a tablet?
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Which process is specifically associated with the use of low molecular weight lipids for coating?
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Which method of microencapsulation involves the dissolution of polymers in water or solvent?
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What primary factor influences the rate of penetration of dissolution fluid into a compressed tablet's matrix?
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Which of the following processes does not use water soluble polymers for coating?
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What is a key advantage of osmotic controlled delivery systems?
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Which of the following parameters affects the release rate in osmotic systems?
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Which statement best describes the release mechanism of osmotic controlled delivery systems?
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What is a characteristic feature of the Single-composition osmotic tablet (SCOT)?
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What factor influences the choice of membrane-forming polymers in osmotic systems?
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Which drug mentioned is an example of a self-emulsifying osmotic pump (SEOP)?
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In osmotic delivery systems, the release rate is not affected by which of the following?
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What characteristic of osmotic delivery systems allows for delayed release functionality?
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Which type of drugs are unsuitable for gastroretentive drug delivery systems?
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What is a common method to increase the gastric residence time of dosage forms?
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Which mechanism is employed in size increasing systems for gastroretentive drug delivery?
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What characteristic should a gastroretentive system have to avoid accumulation in the stomach after multiple doses?
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Which of the following materials is used in effervescent floating systems for gastroretentive drug delivery?
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Which class of agents is commonly used in bioadhesive systems for gastroretentive formulations?
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What is the main role of high density systems in gastroretentive drug delivery?
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What happens to the dosage form when it is immersed in the buffer at 37ºC in effervescent floating systems?
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Which of the following polymers is NOT used as an enteric polymer?
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What is a key characteristic of controlled release drug delivery systems?
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Which term is synonymous with both 'controlled release' and 'prolonged release'?
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In a sustained release formulation, how is the initial dose typically administered?
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What distinguishes controlled release from sustained release dosages?
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Which of the following statements about enteric coated tablets is true?
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What kind of drug delivery does the term 'sustained release' imply?
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Why is controlled release considered advantageous?
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Study Notes
Bioavailability Fundamentals
- Bioavailability is the proportion of a drug that reaches the bloodstream after administration.
- Intravenous (IV) administration results in 100% bioavailability as the drug enters the bloodstream directly.
- Other routes of administration involve absorption, where the drug must pass through barriers before reaching the bloodstream.
BCS Classification of Drugs
- Biopharmaceutical Classification System (BCS) categorizes drugs based on their solubility and permeability.
- Class I Drugs: High solubility, high permeability, well-absorbed.
- Class II Drugs: Low solubility, high permeability, absorption rate limited by dissolution.
- Class III Drugs: High solubility, low permeability, absorption rate limited by membrane permeability.
- Class IV Drugs: Low solubility, low permeability, absorption rate limited by both factors.
In Vitro Dissolution Testing
- Dissolution Testing is a critical component of drug product development to ensure quality.
- USP (United States Pharmacopeia) provides detailed guidelines for conducting dissolution testing.
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Dissolution testing parameters:
- Dissolution medium type (pH, ionic strength)
- Apparatus type (rotating basket or paddle)
- Sampling time intervals
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Dissolution Test Objectives:
- Determine drug release kinetics
- Ensure consistency between batches of drug products
- Meet regulatory requirements.
USP-Approved Dissolution Apparatus
- Apparatus 1 (Rotating Basket): Rotates at specific rpm, suitable for harsh media.
- Apparatus 2 (Paddle): Rotates at specific rpm, suitable for harsh media.
Cell Culture Model for Permeation Studies
- Caco-2 Monolayer: Utilizes differentiated human colon adenocarcinoma cells to model drug permeation across the intestinal mucosa.
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Monolayer Characteristics:
- Resembles small intestinal cells with microvilli, transporter systems, and tight junctions.
- 15-21 days to form properly.
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Integrity Check:
- Non-permeation of a marker molecule or by measuring transepithelial electrical resistance (TEER).
Oral Bioavailability Factors
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Physiological Factors:
- pH variations in the gastrointestinal tract affect drug ionization and dissolution.
- Food consumption alters gastrointestinal motility and drug absorption.
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Drug Factors:
- Lipinski's Rule of Five: Predicts oral absorption based on drug properties.
- Molecular Weight: High molecular weight drugs may have poor absorption.
- LogP: High LogP values indicate high lipophilicity, potentially affecting membrane permeation.
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Excipient Effects:
- Excipients can modify drug absorption rates and extent.
- Diluents can affect drug dissolution.
- Lubricants can impact tablet disintegration.
- Disintegrants enhance drug dissolution.
Approaches for Improving Oral Bioavailability
-
Formulation Strategies:
- Nanoparticle formulation
- Microsphere formulation
- Drug delivery systems
- Salt formation
- Prodrug development
Comparative Release from IR and CR Formulations
- Procainamide plasma concentrations are higher with slow-release tablets taken every 8 hours than with conventional tablets taken every 4 hours
Meltrex Technology® for Controlled Release
- A hot melt extrusion to tablet technology
- Suitable for pharmaceutical formulations because it is a solvent-free green formulation technology
- Well-established process in the polymer, food, and plastic industries
- In-line PAT can be used to monitor product quality
- Easily scalable
Alcohol Induced Dose Dumping
- Sustained-release formulations can be affected by the intake of alcohol, leading to "dose dumping".
- Dose dumping is when the integrity of the barrier controlling the release rate is breached, resulting in increased exposure to the active drug, possible safety issues, and changes in clinical efficacy.
Dissolution Controlled Formulations: Limitations
- A major disadvantage of matrix devices is that drug release rate continuously decreases with time due to increased diffusional distance and decreased surface area at the penetrating solvent front.
Diffusion Controlled Release Formulations
- It is a major process for absorption in which no energy is required.
- Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attained.
- Release rate is directly proportional to the concentration gradient across the membrane.
- Release rate is determined by its diffusion through a water-insoluble polymer.
- Two types of diffusion devices:
- Reservoir diffusion system
- Matrix diffusion system
Diffusion Controlled Release Formulations: Reservoir Devices
- Drug is encased in a water-insoluble polymeric material.
- Drug will partition into the membrane and exchange with the surrounding fluid.
- The amount of drug released, the release rate dM/dt is given by the equation:
where: - A is the area - D is the diffusion coefficient - K is the partition coefficient of drug between the membrane and drug core - ℓ is the diffusional path length (thickness of coat in the ideal case) - C is the concentration difference across the membrane.dM/dt = ADK C/ ℓ
Diffusion CR Formulations: Reservoir Devices Preparation
- Drug containing cores in tablets
- Compression coating of drug cores
- Air suspension coating of drug pellets
- Drug particles: Microencapsulation of drug particles to be incorporated into tablets or capsules
Diffusion CR Formulations: Reservoir Devices Release Rate
- Several factors affect the release rate.
- Partition of drug between membrane and core
- Thickness of the coating
- Polymer ratio in the coating
- Hardness of microcapsules
Ion Exchange Resins
- Quaternary ammonium anion exchange resin
- Used in reducing blood cholesterol level
Osmotic Controlled Delivery Systems
- Osmotic pressure is the driving force that generates constant drug release.
- These systems are not affected by physiological factors such as type of food intake, gastric pH, and patient-to-patient variability.
- The delivery strategy and release profile can be customized to suit various APIs with a wide range of thermodynamic properties.
- Due to this uniqueness, osmotic systems have witnessed increasing interest and the number of marketed products has doubled in the past decades.
Osmotic Controlled Delivery Systems: Basic Principles
-
When exposed to water or body fluid, water will flow into the core due to an osmotic pressure difference across the coating membrane.
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Under this osmotic pressure gradient, the volume flow of water into the core reservoir, dV/dt, is expressed as:
dV/dt = (Ak/h) ( - P)where: - A, k and h are the area, membrane permeability, and thickness, respectively - is the osmotic pressure difference - P is the hydrostatic pressure difference.
- If the orifice is sufficiently large, the hydrostatic pressure difference will be small compared to the osmotic pressure difference, and the equation becomes:
dV/dt = (Ak/h) - Drug is pumped out of the system through the orifice at a controlled rate, dM/dt which is equal to the volume flow rate of water into the core multiplied by the drug concentration, Cs.
Methylphenidate HCL Triple layer Osmotic Pump: Concerta®
- Osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat.
- The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components.
- There is a precision-laser drilled orifice on the drug-layer end of the tablet.
- In an aqueous environment, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate.
- Water permeates through the membrane into the tablet core.
- As the osmotically active polymer excipients expand, methylphenidate is released through the orifice.
Gastroretentive Systems
- The maximum achievable sustained drug release is subject to inter-individual variations with an average gastrointestinal (GI) transit time of around 24 h in humans.
- Retention of oral dosage forms in the upper GIT causes prolonged contact time of drug with the GI mucosa, leading to higher bioavailability, therapeutic efficacy, reduced time intervals for drug administration, potentially reduced dose size, and thus improved patient compliance.
Gastroretentive Systems: Selection of APIs
- Gastroretentive DDSs exhibiting controlled drug release are significantly important for drugs that are:
- Acting locally in the stomach (e.g., antibiotics against Helicobacter Pylori, antacids and misoprostol)
- Absorbed incompletely due to a relatively narrow window of absorption in the GIT
- Unstable in the intestinal or colonic environment
- Exhibit low solubility at high pH values
Gastroretentive DDS, are not suitable for drugs that:
- May cause gastric lesions
- Are unstable in the strong acidic pH of the stomach
- Are absorbed throughout the gastrointestinal tract
Gastroretentive Systems: Types
- The most common approaches used to increase the gastric residence time of pharmaceutical dosage forms include:
- Co-administration of the DDS with pharmacological agents that slow gastric motility
- Bioadhesive systems
- Size increasing systems
- Density controlled systems
Gastroretentive Systems: Size increasing systems
- To facilitate swallowing, the dosage form should have an initially small size.
- Once in the stomach, the dosage forms should quickly increase in size to prevent premature emptying through the pylorus.
- To avoid accumulation following multiple administrations, the system should be cleared from the stomach after a predetermined time interval.
- The dosage form should have no effect on gastric motility or emptying process.
- The increase in the systems’ size can be based on several principles including expansion due to swellable excipients or unfolding and/ or shape modification (to complex geometric shapes) in the stomach.
Gastroretentive Systems: Effervescent Floating
- The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid is divided into 2 sublayers to avoid direct contact between the 2 agents.
- These sublayers are surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac.
- When this system is immersed in the buffer at 37ºC, it settles down and the solution permeates into the effervescent layer through the outer swellable membrane.
Enteric Polymers
- Enteric polymers are insoluble at a pH of 6 or below (stomach) but become soluble at a pH above 6 (intestine).
- The functional group ionizes at higher pH, allowing it to solubilize the polymer.
- Enteric coated tablets are coated with these polymers, preventing the drug from being released in the stomach.
- Common enteric polymers include Cellulose acetate phthalate, Hydroxypropyl methyl cellulose phthalate, Hydroxypropyl methyl cellulose acetate-succinate, Polyvinyl acetate phthalate, and Methacrylic acid copolymers.
Controlled Release Dosage Forms
- The US Pharmacopoeia defines modified release dosage forms as those that release drugs at a controlled rate and location to achieve therapeutic objectives not offered by conventional dosage forms.
- Controlled release, prolonged release, sustained or slow release, and long-acting are synonymous terms for extended release.
Controlled Release Drug Delivery
- Focuses on delivering the drug at a predetermined rate over a defined period.
- It aims to achieve a constant drug release irrespective of the drug concentration, ideally with a zero-order release.
Sustained Release Dosage Forms
- Characterized by an initial immediate release (loading dose) to rapidly achieve therapeutic efficacy.
- Subsequent slow release (maintenance dose) maintains therapeutic levels for prolonged durations.
- It may or may not be controlled release, implying slow release but not necessarily constant.
Controlled Release Vs Immediate Release
- Consider MEC (Minimum Effective Concentration), MTC (Minimum Toxic Concentration), the therapeutic window, and drug half-life.
Reasons for Controlled Release
- To achieve sustained therapeutic effect.
- To reduce dosing frequency.
- To minimize side effects.
- To improve patient compliance.
- To target specific sites of action.
Drug Release Mechanisms
- Microencapsulated Particles/Coated Granules: The drug is compressed with a slowly dissolving carrier.
- Coating: Individual drug particles or granules are coated with a slow-dissolving material. This is done by varying the coating thickness and composition to control drug release rates.
- Matrix Systems: The drug is compressed into a tablet with a slowly dissolving matrix. This matrix controls the drug dissolution rate by regulating the rate at which the dissolution fluid penetrates the matrix.
-
Osmotic Systems: Drug release rate is directly proportional to the osmotic pressure of the core formulation.
- SCOT (Single-Composition Osmotic Tablet): A single-layer osmotic pump with a porous membrane that accommodates a high drug load.
- SEOP (Self-Emulsifying Elementary Osmotic Pump): An osmotic pump that self-emulsifies in the gastrointestinal tract.
Advantages of Osmotic Controlled Delivery Systems
- Zero-order release
- Capability for pulsed or delayed release.
- Independent of gastric pH and physiological conditions.
- Release mechanism is independent of drug properties.
- High correlation between in vitro and in vivo performance.
Gastroretentive Systems
- Gastric retention systems increase the residence time of the drug in the stomach, enhancing drug absorption.
- Common approaches to achieve gastric retention include:
- Co-administration of pharmacological agents
- Bioadhesive systems
- Size increasing systems
- Density controlled systems
- Effervescent floating systems utilize effervescent agents and swellable polymer membranes to float in the stomach.
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- Effervescent floating Systems: utilizes effervescent agents and swellable polymer membranes to float in the stomach.
- The outer layer of swellable polymer membrane surrounding the effervescent agents controls the release of gas, allowing the tablet to float in the stomach.
- The effervescent agent releases gas, causing the tablet to float.
Example Controlled Release Products
- Procardia XL (Nifedipine): An antihypertensive drug with a half-life of 2 hours. It is practically insoluble in water. Procardia XL utilizes a PPOS (Polymeric Osmotic Pump System) to control the release of Nifedipine.
- Tegretol® XR (Carbamazepine): An anticonvulsant drug with a half-life of 30 hours. It is poorly soluble in water. Tegretol® XR uses a SEOP (Self-Emulsifying Osmotic Pump) to control the release of Carbamazepine.
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Description
This quiz delves into the fundamental concepts of bioavailability and the Biopharmaceutical Classification System (BCS) of drugs. It covers the principles of drug absorption, various administration routes, and the classification of drugs based on solubility and permeability. Test your understanding of these critical pharmacological concepts.
