Fundamentals of Bioavailability and BCS

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What are the two parameters that govern drug absorption in the BCS classification?

Molecular weight and pH level

Solubility and permeability (correct)

Distribution and elimination

Chemical stability and formulation type

Why is dissolution testing significant in drug product development?

To measure the drug's potency

To assess the safety of the drug

To determine the drug's shelf life

To evaluate the release rate of a drug (correct)

What is the difference between absolute bioavailability and relative bioavailability?

Absolute bioavailability measures systemic exposure compared to an intravenous administration, while relative bioavailability is compared to a standard formulation. (correct)

Absolute bioavailability is specific to injectable drugs, and relative bioavailability is for oral doses only.

Absolute bioavailability refers to the total dose of a drug, and relative bioavailability refers only to oral doses.

Absolute bioavailability is the bioavailability in humans, and relative bioavailability is for animal studies.

Which factors affect drug absorption and bioavailability?

Physiological factors and drug formulation characteristics Signup and view all the answers

What is a characteristic feature of USP dissolution studies?

They determine the rate and extent of drug release from its dosage form. Signup and view all the answers

What is the percentage of bioavailability for drugs administered via the intravenous route?

100% Signup and view all the answers

What must occur for any drug administered via routes other than intravenous to enter the bloodstream?

Absorption process Signup and view all the answers

Which of the following best describes absolute bioavailability?

The percentage of the administered dose that reaches the systemic circulation intact Signup and view all the answers

If a drug administered orally has a bioavailability of 80%, what does this indicate?

Less than 100% of the drug reaches systemic circulation Signup and view all the answers

What does an increase in absorption imply regarding drug bioavailability?

Increased systemic circulation of the drug Signup and view all the answers

What is required by the U.S. FDA to control the quality of pharmaceutical products?

Dissolution testing data Signup and view all the answers

Which of the following parameters is NOT specified in the USP drug monographs for dissolution analysis?

Concentration of active ingredients Signup and view all the answers

What is the significance of measuring the time for 75% of the labeled amount of drug to dissolve according to USP guidelines?

To evaluate the drug's release profile Signup and view all the answers

What type of apparatus uses a rotating basket during the dissolution testing process?

Apparatus 1 Signup and view all the answers

Which class of drugs typically has low solubility and low permeability?

Class IV Signup and view all the answers

What mechanism do most drugs use to permeate biological membranes?

Simple diffusion Signup and view all the answers

What condition must the dissolution medium be kept at during testing?

37 °C Signup and view all the answers

What role does a drug's ability to partition into a lipophilic membrane environment play?

It indicates whether the drug can cross the biomembrane Signup and view all the answers

What is a key characteristic of facilitated diffusion?

Is driven by the drug concentration gradient Signup and view all the answers

How does active transport differ from facilitated diffusion?

It can transport substances against their concentration gradient Signup and view all the answers

What is the role of the Caco-2 monolayer in studying drug permeation?

It simulates the physiological conditions of the small intestine Signup and view all the answers

Which statement is true regarding the factors affecting oral bioavailability?

pH variation can impact drug ionization and absorption Signup and view all the answers

What indicates successful formation of a Caco-2 monolayer?

High transepithelial electrical resistance (TEER) Signup and view all the answers

Which concept describes the competitive inhibition related to membrane transporters?

Substrate analogues can inhibit the transport process Signup and view all the answers

During active transport, which of the following is necessary?

Energy to drive the transport process Signup and view all the answers

What happens when the integrity of the Caco-2 monolayer is compromised?

Marker molecules permeate the monolayer Signup and view all the answers

What is the maximum number of hydrogen-bond donors according to Lipinski's Rule of Five for good oral absorption?

5 Signup and view all the answers

Which of the following factors does not predict a compound's pharmacological activity according to Lipinski's Rule of Five?

Pharmacokinetics Signup and view all the answers

What role do excipients play in drug absorption?

They can modify the extent and rate of absorption. Signup and view all the answers

According to Lipinski's Rule of Five, what is the limit for hydrogen-bond acceptors?

10 Signup and view all the answers

What is the maximum molecular weight suggested by Lipinski's Rule of Five to ensure good oral absorption?

500 Signup and view all the answers

Which of the following does NOT represent a common type of drug based on the content?

Enzymes Signup and view all the answers

What is one key purpose of dissolution testing in drug product development?

To assess the rate and extent of drug absorption. Signup and view all the answers

Which of the following describes a scenario where excipients could modify drug absorption?

Selecting a specific disintegrant Signup and view all the answers

What is a key concern when using sustained release formulations in relation to alcohol intake?

Dose dumping due to barrier integrity breach Signup and view all the answers

What technology is employed in Meltrex Technology for controlled release formulations?

Hot melt extrusion Signup and view all the answers

What primary disadvantage is associated with matrix devices in drug release?

Continuous decrease in drug release rate Signup and view all the answers

Which statement about the Meltrex Technology is true?

It offers a solvent-free green formulation technology. Signup and view all the answers

In the context of drug release, what is essential to achieve zero order release from matrix devices?

Selecting a geometry that increases surface area Signup and view all the answers

What is a potential consequence of breaching the release control barrier in sustained release formulations?

Increased exposure to the active drug Signup and view all the answers

What is the main method of drug absorption that requires no energy?

Diffusion-controlled release Signup and view all the answers

Which of the following best describes the scalability of Meltrex Technology?

It allows for easily scalable processes. Signup and view all the answers

What is the main factor that determines the release rate of drug molecules in a diffusion-controlled release formulation?

The diffusion through the polymer material Signup and view all the answers

Which parameter is NOT necessary to maintain for a constant drug release rate from a reservoir device?

Temperature of the environment Signup and view all the answers

What role does the polymer material play in a reservoir diffusion system?

It acts as a barrier to control drug release Signup and view all the answers

Which of the following factors does NOT affect the release rate of a drug from a reservoir device?

Rate of drug absorption in the digestive tract Signup and view all the answers

What equation describes the release rate of a drug from a diffusion-controlled release formulation?

dM/dt = ADK ΔC / ℓ Signup and view all the answers

In a matrix diffusion system, what primarily influences drug release?

Interactions between drug and polymer matrix Signup and view all the answers

What is one reason why a combination of dissolution and diffusion may occur in microencapsulated material?

The encapsulation material may dissolve along with diffusion Signup and view all the answers

How is the partition coefficient significant in the context of diffusion-controlled release formulations?

It influences the rate of drug release across the membrane Signup and view all the answers

What is the primary function of cholestyramine in pharmaceuticals?

Reduce blood cholesterol levels Signup and view all the answers

Which statement accurately describes the action of osmotic controlled delivery systems?

They utilize osmotic pressure as the main drive for drug release. Signup and view all the answers

What determines the volume flow of water into the core of an osmotic system?

The osmotic pressure difference and membrane characteristics Signup and view all the answers

Which of the following is a cation exchange resin mentioned?

Sulfonated styrene Signup and view all the answers

What factor is crucial to ensuring that the hydrostatic pressure difference is minimized in an osmotic system?

The osmotic pressure difference must be substantially elevated. Signup and view all the answers

What is colestipol primarily used for?

Removing bile acids from the body Signup and view all the answers

Which property is associated with osmotic delivery systems?

They provide a customizable release profile for various APIs. Signup and view all the answers

What parameter is NOT included in the equation for volume flow of water into the core of an osmotic system?

Concentration of the drug, Cs Signup and view all the answers

What is the primary function of the push layer in the trilayer core of Concerta®?

To expand and release the drug through the orifice Signup and view all the answers

Which statement accurately describes the initial release of methylphenidate in Concerta®?

It involves the dissolution of an immediate-release overcoat within one hour. Signup and view all the answers

What is a benefit of gastroretentive drug delivery systems?

Enhanced therapeutic efficacy through prolonged contact time Signup and view all the answers

Which type of drug is most appropriate for use in gastroretentive drug delivery systems?

Drugs that are unstable in the intestinal environment Signup and view all the answers

What characteristic is essential for the orifice of Concerta® to function properly?

It needs to be precision-laser drilled to control drug release Signup and view all the answers

How does the average gastrointestinal transit time impact drug release from gastroretentive systems?

Longer transit times provide extended therapeutic effects. Signup and view all the answers

Why are certain drugs selected for gastroretentive delivery systems?

They have specific sites of action local to the stomach. Signup and view all the answers

What role does water play in the drug release mechanism of Concerta®?

It activates the push layer to begin drug release. Signup and view all the answers

Which type of gastroretentive system uses polymers that adhere to the stomach lining?

Bioadhesive systems Signup and view all the answers

Which mechanism is least effective in increasing gastric residence time for drugs?

Co-administration with agents that speed up gastric emptying Signup and view all the answers

What is a key characteristic of size increasing gastroretentive systems?

They should not affect gastric motility or emptying. Signup and view all the answers

Which of the following substances is NOT suitable for gastroretentive DDS?

Drugs stable in acidic pH Signup and view all the answers

How do effervescent floating systems maintain their position in the stomach?

Through the formation of gas bubbles Signup and view all the answers

Which of the following describes an appropriate action to avoid premature emptying of a gastroretentive dosage form?

Ensuring the dosage form expands in size Signup and view all the answers

What is one of the components used in an effervescent floating system?

Sodium bicarbonate Signup and view all the answers

Which characteristic of a gastric retentive system enhances its ability to be cleared from the stomach after multiple uses?

It should not adhere to the stomach lining. Signup and view all the answers

What is the primary advantage of using microencapsulation for drug delivery?

It forms a protective barrier to control drug release. Signup and view all the answers

In the Noyes-Whitney equation, what does 'D' represent?

Diffusion coefficient Signup and view all the answers

Which factor can be varied to control the rate of drug release in coated granules?

Thickness of the coating Signup and view all the answers

What is one key characteristic of microencapsulated particles?

They can be either solid, liquid, or gas. Signup and view all the answers

How does the composition of the coating material impact drug release?

It determines the interactions with physiological fluids. Signup and view all the answers

Which method utilizes oppositely charged aerosols for microencapsulation?

Electrostatic method Signup and view all the answers

What characteristic of a tablet matrix primarily controls the rate of drug dissolution?

Porosity of the tablet matrix Signup and view all the answers

Which coating material is suitable for interfacial polymerization in microencapsulation?

Water soluble and insoluble monomers Signup and view all the answers

Which method can be used to control drug release by manipulating the effective porosity of a tablet?

Matrix dissolution Signup and view all the answers

Which process is specifically associated with the use of low molecular weight lipids for coating?

Hot melt Signup and view all the answers

Which method of microencapsulation involves the dissolution of polymers in water or solvent?

Precipitation Signup and view all the answers

What primary factor influences the rate of penetration of dissolution fluid into a compressed tablet's matrix?

Surface area and porosity Signup and view all the answers

Which of the following processes does not use water soluble polymers for coating?

Hot melt Signup and view all the answers

What is a key advantage of osmotic controlled delivery systems?

Achievement of zero order release Signup and view all the answers

Which of the following parameters affects the release rate in osmotic systems?

Membrane thickness Signup and view all the answers

Which statement best describes the release mechanism of osmotic controlled delivery systems?

It is independent of the properties of the drug. Signup and view all the answers

What is a characteristic feature of the Single-composition osmotic tablet (SCOT)?

It includes a porous membrane for high drug loading. Signup and view all the answers

What factor influences the choice of membrane-forming polymers in osmotic systems?

Membrane permeability adjustments Signup and view all the answers

Which drug mentioned is an example of a self-emulsifying osmotic pump (SEOP)?

Carbamazepine Signup and view all the answers

In osmotic delivery systems, the release rate is not affected by which of the following?

Drug's mechanism of action Signup and view all the answers

What characteristic of osmotic delivery systems allows for delayed release functionality?

Controlled osmotic pressure Signup and view all the answers

Which type of drugs are unsuitable for gastroretentive drug delivery systems?

Drugs absorbed primarily in the small intestine Signup and view all the answers

What is a common method to increase the gastric residence time of dosage forms?

Administering with agents that slow gastric motility Signup and view all the answers

Which mechanism is employed in size increasing systems for gastroretentive drug delivery?

Expanding due to swellable excipients or shape modification Signup and view all the answers

What characteristic should a gastroretentive system have to avoid accumulation in the stomach after multiple doses?

A clearance mechanism from the stomach after a predetermined time Signup and view all the answers

Which of the following materials is used in effervescent floating systems for gastroretentive drug delivery?

Sodium bicarbonate and tartaric acid Signup and view all the answers

Which class of agents is commonly used in bioadhesive systems for gastroretentive formulations?

Bioadhesive polymers like sodium carboxymethyl cellulose Signup and view all the answers

What is the main role of high density systems in gastroretentive drug delivery?

To ensure prolonged gastric residence by settling at the bottom of the stomach Signup and view all the answers

What happens to the dosage form when it is immersed in the buffer at 37ºC in effervescent floating systems?

The solution permeates, leading to swelling and buoyancy Signup and view all the answers

Which of the following polymers is NOT used as an enteric polymer?

Eudragit L100 Signup and view all the answers

What is a key characteristic of controlled release drug delivery systems?

They deliver the drug in a predetermined rate over time. Signup and view all the answers

Which term is synonymous with both 'controlled release' and 'prolonged release'?

Sustained release Signup and view all the answers

In a sustained release formulation, how is the initial dose typically administered?

As a loading dose followed by a maintenance dose. Signup and view all the answers

What distinguishes controlled release from sustained release dosages?

Controlled release is characterized by zero order release. Signup and view all the answers

Which of the following statements about enteric coated tablets is true?

They are insoluble at pH 6 or below but dissolve above pH 6. Signup and view all the answers

What kind of drug delivery does the term 'sustained release' imply?

It releases the drug slowly over a specified period. Signup and view all the answers

Why is controlled release considered advantageous?

It provides therapeutic levels of drug without concentration variation. Signup and view all the answers

What is the primary component in the core of the Implanon implant?

40% ethylene vinyl acetate copolymer Signup and view all the answers

Which sterilization method uses dry, saturated steam under pressure?

Moist heat sterilization Signup and view all the answers

Which of the following accurately describes the Sterility Assurance Level (SAL)?

It defines the acceptable probability of one viable microorganism in certain drug products. Signup and view all the answers

Which of the following methods is NOT a common sterilization method mentioned?

Ionization sterilization Signup and view all the answers

What is a key feature of the sterile filtration method?

It filters the preparation and incubates the filter to assess microorganism counts. Signup and view all the answers

What is one primary characteristic of injectables compared to peroral routes?

Higher complexity during manufacturing Signup and view all the answers

Which of the following best describes the openings in lymphatic capillaries?

Approximately 15-20 nm width Signup and view all the answers

What is the primary challenge related to long-acting injectable formulations?

Complexity in development Signup and view all the answers

What effect do anti-drug antibodies (ADAs) have on pharmacokinetics?

Significantly complicate their predictability Signup and view all the answers

What is required for injections to ensure their quality?

Clarity and freedom from visible particles Signup and view all the answers

Which factor significantly complicates the formation of long-acting injectables?

Challenges in maintaining sterility Signup and view all the answers

How do higher molecular weight molecules compare in diffusion through tissues?

They cannot diffuse through tissues but can enter lymphatic capillaries Signup and view all the answers

What is one of the major safety concerns for injectable formulations?

Potential for physical and chemical contamination Signup and view all the answers

What does the necessity for sterile formulations imply for injectables?

Additional regulatory oversight is required Signup and view all the answers

What is the typical osmolarity range for injections that are considered acceptable and non-irritating?

~225-430 mOsmol Signup and view all the answers

Which of the following buffers has a pKa value closest to 6.4?

Citrate buffer Signup and view all the answers

What is the role of sodium chloride in the formulation of injections?

To adjust tonicity Signup and view all the answers

Which of the following statements about the use of preservatives in injections is correct?

Multidose containers may contain preservatives. Signup and view all the answers

What is the function of buffer salts such as histidine or citrate in injection formulations?

Maintaining pH stability Signup and view all the answers

For a multidose injection container with a volume greater than 15 mL, what is the requirement regarding preservatives?

Preservatives are optional Signup and view all the answers

Which of the following is NOT a commonly used pH adjusting agent for injections?

Acetic acid Signup and view all the answers

What is the maximum volume typically contained in a single-dose vial for injections?

15 mL Signup and view all the answers

Which of the following small molecules is commonly used to modify tonicity in injections?

Mannitol Signup and view all the answers

Which buffered condition is associated with a pKa of 7.2?

Phosphate buffer Signup and view all the answers

What is the primary reason for the high cost of production associated with parenteral drug delivery?

Stringent sterility requirements Signup and view all the answers

Which of the following administration routes typically has the least stringent requirements?

Subcutaneous (SC) Signup and view all the answers

What type of parenteral preparation involves administering sterile solutions over an extended period?

Infusions Signup and view all the answers

In the context of parenterals, what is the role of excipients?

To stabilize the formulation and enhance delivery Signup and view all the answers

Which of the following is NOT a type of parenteral preparation?

Topical ointments Signup and view all the answers

Which parameter is crucial for the administration of intravenous (IV) drugs?

Rate of infusion Signup and view all the answers

How is sterility typically achieved in the production of parenteral products?

Using a clean room or closed processing systems Signup and view all the answers

What does the volume of distribution indicate about a drug?

The concentration of the drug in the blood plasma Signup and view all the answers

Which administration route accounts for the highest percentage of drug administration according to the given content?

Intravenous Signup and view all the answers

What is a characteristic difference between MyocetTM and DoxilTM formulations?

MyocetTM contains almost no unbound doxorubicin Signup and view all the answers

What is the primary significance of IV injections in pharmacokinetics?

They are used to measure volume of distribution Signup and view all the answers

Which factor contributes to the higher tolerance of SC/IM regarding specifically mentioned solutions?

Osmotic pressure differences Signup and view all the answers

What type of drug administration is most commonly linked with a 35% presence according to the data presented?

Subcutaneous Signup and view all the answers

Which statement about liposomes is correct based on the content?

They assist in reducing systemic drug exposure Signup and view all the answers

How do SC/IM routes handle pH variations compared to other routes?

They have much higher tolerance to pH variations Signup and view all the answers

What percentage of drug administration routes is represented by oral administration?

4% Signup and view all the answers

Which parenteral administration method typically requires stricter sterility requirements?

Intravenous administration Signup and view all the answers

What is a common reason for the high production cost of parenteral drug delivery systems?

Strict sterility requirements Signup and view all the answers

What types of formulations can be delivered using parenteral preparations?

Sterile implants and powders Signup and view all the answers

What role do excipients play in injectable formulations?

They assist in drug solubility and stability Signup and view all the answers

Which administration site generally allows for a slower onset of action compared to intravenous injections?

Subcutaneous injection Signup and view all the answers

What is a potential use of depot formulations in parenteral drug delivery?

To provide sustained release of poorly permeable drugs Signup and view all the answers

Which statement accurately describes a characteristic of parenteral drug delivery?

It can be used for both emergency and long-term treatments Signup and view all the answers

What does the term 'volume of distribution' in pharmacokinetics indicate?

The extent to which a drug is present in blood plasma Signup and view all the answers

Which administration route has the highest percentage of usage in biologics?

Intravenous Signup and view all the answers

What differentiates MyocetTM from DoxilTM in terms of doxorubicin?

DoxilTM has almost no unbound doxorubicin Signup and view all the answers

What type of injection is commonly used to determine the volume of distribution?

Intravenous injection Signup and view all the answers

What is a primary characteristic of Implants in pharmaceutical applications?

They are solid preparations suitable for parenteral implantation. Signup and view all the answers

Which of the following does NOT represent a factor with much higher tolerance in SC/IM routes?

Stability in acidic pH Signup and view all the answers

What percentage of intramuscular injections is related to biologics?

15% Signup and view all the answers

What does the Sterility Assurance Level (SAL) signify in pharmaceutical sterilization?

The probability of a viable microorganism in drug products. Signup and view all the answers

In pharmacology, which factor primarily influences the choice of administration route for biologics?

Bioavailability of the drug Signup and view all the answers

Which of the following is NOT a common sterilization method?

Iodine infusion Signup and view all the answers

Which formulation of doxorubicin is characterized by a significant amount of unbound drug?

MyocetTM Signup and view all the answers

What distinguishes the core composition of Implanon?

40% ethylene vinyl acetate copolymer and etonorgestrel. Signup and view all the answers

Which injection type represents the least percentage of biologics administration routes?

Topical Signup and view all the answers

What is the typical osmolarity range considered acceptable to avoid pain or irritation during injection?

225-430 mOsmol Signup and view all the answers

Which pH adjusting agent is commonly used to increase acidity in aqueous solutions?

Hydrochloric acid Signup and view all the answers

What is the primary characteristic of a single dose vial compared to a multidose container?

Contains no preservatives Signup and view all the answers

Which of the following buffers has a pKA2 value closest to neutral pH?

Phosphate buffer (pKA2 = 7.2) Signup and view all the answers

In the context of injections, what is the primary purpose of adding tonicity agents like sodium chloride?

To ensure compatibility with body fluids Signup and view all the answers

Which component is not typically found in a multi-dose container?

Single-use only Signup and view all the answers

What is the typical consequence of using a high concentration of dextrose as an excipient in injections?

Increased osmolarity Signup and view all the answers

Which of the following is considered a characteristic of buffered injections?

They maintain a stable pH range Signup and view all the answers

What component can serve as an excipient to modify the physical properties of injections without being an active drug?

Dextrose Signup and view all the answers

What is one potential risk of not including a preservative in a multidose vial?

Microbial contamination Signup and view all the answers

Which excipient is primarily responsible for stabilizing insulin solutions?

Zinc chloride Signup and view all the answers

What is the role of metacresol in insulin solutions?

Preservative Signup and view all the answers

Which of the following is used as a steric stabilizer in formulations?

Dextran Signup and view all the answers

In the formulation of antibody concentrates, which excipient is used as a pH buffer?

Tri-sodium citrate dihydrate Signup and view all the answers

What defines an infusion in pharmaceutical terms?

A sterile, aqueous solution or emulsion made isotonic with blood Signup and view all the answers

Which excipient in insulin solutions is specifically used for tonicity?

Glycerol Signup and view all the answers

What is a characteristic feature of powders for injections or infusions?

They form clear solutions or uniform suspensions when reconstituted. Signup and view all the answers

Which ingredient is used in insulin formulations solely for pH adjustment?

HCl Signup and view all the answers

What is true about the formulation of concentrates for injections or infusions?

They must be diluted with a prescribed liquid before administration. Signup and view all the answers

Which of the following accurately describes the primary function of preservatives in pharmaceutical formulations?

To prevent microbial growth Signup and view all the answers

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.
Dissolution testing parameters:
- Dissolution medium type (pH, ionic strength)
- Apparatus type (rotating basket or paddle)
- Sampling time intervals
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.
Monolayer Characteristics:
- Resembles small intestinal cells with microvilli, transporter systems, and tight junctions.
- 15-21 days to form properly.
Integrity Check:
- Non-permeation of a marker molecule or by measuring transepithelial electrical resistance (TEER).

Oral Bioavailability Factors

Physiological Factors:
- pH variations in the gastrointestinal tract affect drug ionization and dissolution.
- Food consumption alters gastrointestinal motility and drug absorption.
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.
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:
```
dM/dt = ADK C/ ℓ
```
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.

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.
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.