This document discusses bioavailability and bioequivalence. It defines bioavailability as the rate and extent of drug absorption into systemic circulation from its dosage form. Bioequivalence is established when two similar dosage forms reach systemic circulation at the same relative rate and extent. The objectives, significance, and various study designs of bioavailability testing are described, including absolute vs relative bioavailability. Methods for measuring bioavailability and various in vitro drug dissolution models are also summarized.
This document discusses kinetics of multiple dosing, drug accumulation, and concepts of loading and maintenance doses. It provides definitions and formulas for calculating accumulation factor, steady state levels, loading doses, and maintenance doses. The key points are:
1) Multiple dosing leads to drug accumulation until steady state is reached when the drug entering and leaving the system are equal.
2) Loading doses provide rapid target concentrations while maintenance doses maintain therapeutic levels.
3) Calculations for loading and maintenance doses depend on clearance, volume of distribution, and bioavailability. Maintaining therapeutic levels with minimal fluctuations is the goal of multiple dosing regimens.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
This document discusses bioavailability and bioequivalence concepts including definitions, objectives of bioavailability studies, types of bioavailability studies, and methods of measuring bioavailability. It also covers bioequivalence experimental study designs including completely randomized, randomized block, repeated measures, and Latin square designs. In vitro dissolution studies and developing in vitro-in vivo correlations to help assess bioavailability without human studies are also summarized.
This document discusses the one compartment model for intravenous infusion. It explains that IV infusion maintains a stable drug concentration over a long period by administering the drug at a constant zero-order rate. The key aspects covered include:
- Reaching a steady state concentration where the infusion rate equals the elimination rate.
- Calculating the steady state concentration, elimination rate constant, and other pharmacokinetic parameters.
- The time required to reach steady state being dependent on the drug's half-life, not the infusion rate.
- Using a loading dose for drugs with long half-lives to quickly reach the steady state concentration upon starting infusion.
Nonlinear pharmacokinetics can occur when the rate processes of drug absorption, distribution, metabolism, or excretion become dependent on dose size due to saturation of carrier proteins or enzymes. Some specific causes of nonlinearity include saturation of transporters during drug absorption, saturation of plasma protein binding sites or tissue binding sites during distribution, capacity-limited drug metabolism by enzyme saturation, and saturation of active tubular secretion or reabsorption processes during excretion. The Michaelis-Menten equation can describe the kinetics of these saturable, capacity-limited processes.
This document appears to be 3 scanned pages from a mobile device application called CamScanner. The pages are blank except for a watermark indicating they were scanned with CamScanner. In summary, the document provides no substantive information due to being 3 blank scanned pages from a mobile scanning application.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
This document discusses in vitro-in vivo correlations (IVIVCs). It defines IVIVC as a predictive mathematical model relating an in vitro property (e.g. dissolution rate) to an in vivo response (e.g. absorption rate). The document outlines the significance of IVIVCs in reducing bioequivalence studies and supporting biowaivers. It describes different levels of IVIVC (A, B, C) and parameters that can be correlated (dissolution rate to absorption rate; percent dissolved to percent absorbed). The document provides examples of IVIVC case studies and concludes that current regulatory guidelines only apply to oral dosage forms, while further research is needed to develop IVIVCs for other drug products.
This document discusses kinetics of multiple dosing, drug accumulation, and concepts of loading and maintenance doses. It provides definitions and formulas for calculating accumulation factor, steady state levels, loading doses, and maintenance doses. The key points are:
1) Multiple dosing leads to drug accumulation until steady state is reached when the drug entering and leaving the system are equal.
2) Loading doses provide rapid target concentrations while maintenance doses maintain therapeutic levels.
3) Calculations for loading and maintenance doses depend on clearance, volume of distribution, and bioavailability. Maintaining therapeutic levels with minimal fluctuations is the goal of multiple dosing regimens.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
This document discusses bioavailability and bioequivalence concepts including definitions, objectives of bioavailability studies, types of bioavailability studies, and methods of measuring bioavailability. It also covers bioequivalence experimental study designs including completely randomized, randomized block, repeated measures, and Latin square designs. In vitro dissolution studies and developing in vitro-in vivo correlations to help assess bioavailability without human studies are also summarized.
This document discusses the one compartment model for intravenous infusion. It explains that IV infusion maintains a stable drug concentration over a long period by administering the drug at a constant zero-order rate. The key aspects covered include:
- Reaching a steady state concentration where the infusion rate equals the elimination rate.
- Calculating the steady state concentration, elimination rate constant, and other pharmacokinetic parameters.
- The time required to reach steady state being dependent on the drug's half-life, not the infusion rate.
- Using a loading dose for drugs with long half-lives to quickly reach the steady state concentration upon starting infusion.
Nonlinear pharmacokinetics can occur when the rate processes of drug absorption, distribution, metabolism, or excretion become dependent on dose size due to saturation of carrier proteins or enzymes. Some specific causes of nonlinearity include saturation of transporters during drug absorption, saturation of plasma protein binding sites or tissue binding sites during distribution, capacity-limited drug metabolism by enzyme saturation, and saturation of active tubular secretion or reabsorption processes during excretion. The Michaelis-Menten equation can describe the kinetics of these saturable, capacity-limited processes.
This document appears to be 3 scanned pages from a mobile device application called CamScanner. The pages are blank except for a watermark indicating they were scanned with CamScanner. In summary, the document provides no substantive information due to being 3 blank scanned pages from a mobile scanning application.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
This document discusses in vitro-in vivo correlations (IVIVCs). It defines IVIVC as a predictive mathematical model relating an in vitro property (e.g. dissolution rate) to an in vivo response (e.g. absorption rate). The document outlines the significance of IVIVCs in reducing bioequivalence studies and supporting biowaivers. It describes different levels of IVIVC (A, B, C) and parameters that can be correlated (dissolution rate to absorption rate; percent dissolved to percent absorbed). The document provides examples of IVIVC case studies and concludes that current regulatory guidelines only apply to oral dosage forms, while further research is needed to develop IVIVCs for other drug products.
Bioavailability , absolute bioavalability, relative bioavailability, Purpose ...Manikant Prasad Shah
1) Bioavailability studies assess the rate and extent of drug absorption from dosage forms. They are important for developing new drug products and formulations to determine therapeutic effectiveness.
2) There are two types of bioavailability - absolute compares drug absorption from a non-IV route to IV, relative compares absorption between formulations.
3) Methods to assess bioavailability include pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies, and pharmacodynamic methods like measuring pharmacological or therapeutic responses.
This document discusses measurements of bioavailability. It defines bioavailability and bioequivalence. There are two main methods to measure bioavailability - pharmacokinetic and pharmacodynamic. Pharmacokinetic methods include plasma level time studies and urinary excretion studies which measure parameters like Cmax, Tmax, and AUC from plasma data or urinary excretion rate and amount excreted from urine data. Pharmacodynamic methods include measuring acute pharmacological responses or therapeutic responses but have disadvantages like variable individual responses.
The document discusses nonlinear pharmacokinetics and chronopharmacokinetics. Nonlinear pharmacokinetics occurs when the body's absorption, distribution, metabolism, or excretion of a drug becomes saturated at higher doses. This can cause the rate of drug elimination to decrease. Examples of processes that can become saturated include drug metabolism and renal excretion. Circadian rhythms can also impact drug pharmacokinetics by influencing absorption, distribution, metabolism, and excretion over 24-hour periods. Accounting for these temporal changes can improve drug therapy for circadian phase-dependent diseases.
Bioavailability and bioequivalence studies are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability measures the rate and amount of drug that reaches systemic circulation, while bioequivalence demonstrates that generic and brand name products have comparable rates and extents of absorption. Well-designed pharmacokinetic studies are commonly used to assess bioequivalence by comparing AUC and Cmax of test and reference products. Factors like dosage form, solubility, transit time and metabolism can influence bioavailability, so studies may be necessary after manufacturing changes or for different routes of administration. Guidelines regulate bioequivalence testing to allow approval of lower-cost generic drugs while maintaining therapeutic equivalence.
Methods of enhancing bioavailability of drugsDebasish Ghadei
This document discusses various approaches to enhancing the bioavailability of drugs, including enhancing drug solubility, permeability, stability, and gastrointestinal retention. It describes how bioavailability can be improved by increasing a drug's dissolution rate through methods like micronization, nanosuspensions, and use of surfactants. Permeability can be enhanced using lipid technologies, ion pairing, or penetration enhancers. Stability can be improved with enteric coatings or complexation. Gastrointestinal retention time can be lengthened to boost absorption.
ONE COMPARTMENT OPEN MODEL (I.V INFUSION) (Contact me: dr.m.bharathkumar@gmai...DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food items purchased including eggs, milk, bread, bananas, and ground beef. The total for the grocery receipt comes to $36.87. The receipt provides details of the date, time, payment method, and store number for the transaction.
Bioavailability is defined as the rate and extent of absorption of a drug from its dosage form and the amount available at the site of action. It depends on pharmaceutical, patient, and route of administration factors. The objectives of bioavailability studies are to develop new formulations, determine the influence of excipients and other drugs, and control drug product quality. Bioavailability can be assessed using pharmacokinetic methods like plasma concentration-time profiles from single and multiple dose studies, and urinary excretion studies. Key parameters analyzed are Cmax, Tmax, and AUC which indicate rate and extent of absorption. Pharmacodynamic methods like acute pharmacological response and therapeutic response studies can also be used when pharmacokinetic methods are not suitable. In
This document discusses bioequivalence and biopharmaceutics. It defines bioequivalence as the same rate and extent of absorption of the active ingredients in two drug products. Bioequivalence studies compare generic drugs to ensure they are biologically equivalent to the branded drug. In vivo and in vitro bioequivalence studies are described, with in vivo requiring human subjects and in vitro using dissolution testing. Factors that can impact bioequivalence like solubility, excipients, and absorption site are outlined.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
ONE COMPARTMENT OPEN MODEL I.V BOLUS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. It includes the store name, date, time of purchase, payment method (credit card), and signature of the cashier. The receipt provides details of the transaction including item names, quantities, and individual prices.
The document discusses bioavailability studies, which determine the efficiency of drug absorption from different dosage forms and formulations. Key aspects covered include:
- Objectives of bioavailability studies such as determining the influence of excipients and other drugs on absorption during new drug development.
- Factors affecting bioavailability including drug properties, dosage form characteristics, and patient-related factors.
- Methods of measuring bioavailability including plasma concentration-time curves and urinary drug excretion.
- The importance of correlating in vitro dissolution tests to in vivo absorption through levels of in vitro-in vivo correlation (IVIVC).
This document discusses renal and non-renal routes of drug excretion. It describes the key organs and processes involved in excretion, including the nephron in renal excretion and factors that determine if a drug is excreted renally or non-renally. Non-renal excretion includes biliary excretion through the liver and bile ducts. Clearance, excretion ratio, and other pharmacokinetic concepts relating to measurement of excretion are also covered.
This document discusses multicompartment models, including two-compartment models. A two-compartment model classifies body tissues into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues). Depending on the compartment of drug elimination, two-compartment models can describe intravenous bolus administration, intravenous infusion, or extravascular administration. Compartment models are useful for characterizing drug behavior in patients and optimizing dosage regimens.
The document outlines a bioavailability and bioequivalence testing protocol. It begins by defining bioavailability and bioequivalence. It then describes the objectives of bioavailability studies and outlines the key components of a bioavailability study protocol including study design (types of designs discussed are parallel, crossover, Latin square, and balanced incomplete block), subjects, drug administration, sampling, analysis, and statistical analysis. Key aspects of each section are described in detail including considerations for study design, washout periods, single vs. multiple dosing, subject selection, sampling schemes, analysis of biological samples, and use of ANOVA for statistical analysis.
Methods of enhancing Dissolution and bioavailability of poorly soluble drugsRam Kanth
Bioavailability refers to the amount of drug that reaches systemic circulation after administration. It is reduced when drugs are administered orally rather than intravenously due to incomplete absorption and first-pass metabolism. The document discusses several methods for enhancing bioavailability of orally administered drugs with poor solubility or permeability. These include micronization, use of surfactants, salt forms, altering pH, polymorphism, complexation, molecular encapsulation, and forming solid solutions, eutectic mixtures or solid dispersions to improve solubility and dissolution rate.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
This document provides guidelines for conducting bioavailability and bioequivalence studies. It discusses the objectives of such studies, when they are necessary, acceptable study designs, required documentation, and criteria for establishing equivalence between products. The key points covered include:
- The goals of ensuring consistent quality, safety and efficacy of pharmaceuticals.
- Types of studies used, including pharmacokinetic, pharmacodynamic and clinical endpoint trials.
- Standard study designs like randomized crossover trials and considerations for study populations, sampling schedules, and statistical analysis.
- Criteria for waiving BE studies under certain conditions where in vitro dissolution testing can be used instead.
1. The document discusses bioequivalence, which refers to two drug formulations producing comparable levels of the active substance in the bloodstream and providing equivalent therapeutic effects.
2. It defines bioequivalence and outlines the objectives of bioequivalence studies, which are conducted to establish interchangeability between generic and brand-name drugs.
3. The types of bioequivalence studies discussed are in vivo studies, involving human subjects, and in vitro dissolution testing to compare drug release characteristics. Techniques used include blood sampling, analytical methods like HPLC, and statistical tests to determine bioequivalence.
Bioavailability , absolute bioavalability, relative bioavailability, Purpose ...Manikant Prasad Shah
1) Bioavailability studies assess the rate and extent of drug absorption from dosage forms. They are important for developing new drug products and formulations to determine therapeutic effectiveness.
2) There are two types of bioavailability - absolute compares drug absorption from a non-IV route to IV, relative compares absorption between formulations.
3) Methods to assess bioavailability include pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies, and pharmacodynamic methods like measuring pharmacological or therapeutic responses.
This document discusses measurements of bioavailability. It defines bioavailability and bioequivalence. There are two main methods to measure bioavailability - pharmacokinetic and pharmacodynamic. Pharmacokinetic methods include plasma level time studies and urinary excretion studies which measure parameters like Cmax, Tmax, and AUC from plasma data or urinary excretion rate and amount excreted from urine data. Pharmacodynamic methods include measuring acute pharmacological responses or therapeutic responses but have disadvantages like variable individual responses.
The document discusses nonlinear pharmacokinetics and chronopharmacokinetics. Nonlinear pharmacokinetics occurs when the body's absorption, distribution, metabolism, or excretion of a drug becomes saturated at higher doses. This can cause the rate of drug elimination to decrease. Examples of processes that can become saturated include drug metabolism and renal excretion. Circadian rhythms can also impact drug pharmacokinetics by influencing absorption, distribution, metabolism, and excretion over 24-hour periods. Accounting for these temporal changes can improve drug therapy for circadian phase-dependent diseases.
Bioavailability and bioequivalence studies are essential to ensure uniform quality, efficacy, and safety of pharmaceutical products. Bioavailability measures the rate and amount of drug that reaches systemic circulation, while bioequivalence demonstrates that generic and brand name products have comparable rates and extents of absorption. Well-designed pharmacokinetic studies are commonly used to assess bioequivalence by comparing AUC and Cmax of test and reference products. Factors like dosage form, solubility, transit time and metabolism can influence bioavailability, so studies may be necessary after manufacturing changes or for different routes of administration. Guidelines regulate bioequivalence testing to allow approval of lower-cost generic drugs while maintaining therapeutic equivalence.
Methods of enhancing bioavailability of drugsDebasish Ghadei
This document discusses various approaches to enhancing the bioavailability of drugs, including enhancing drug solubility, permeability, stability, and gastrointestinal retention. It describes how bioavailability can be improved by increasing a drug's dissolution rate through methods like micronization, nanosuspensions, and use of surfactants. Permeability can be enhanced using lipid technologies, ion pairing, or penetration enhancers. Stability can be improved with enteric coatings or complexation. Gastrointestinal retention time can be lengthened to boost absorption.
ONE COMPARTMENT OPEN MODEL (I.V INFUSION) (Contact me: dr.m.bharathkumar@gmai...DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food items purchased including eggs, milk, bread, bananas, and ground beef. The total for the grocery receipt comes to $36.87. The receipt provides details of the date, time, payment method, and store number for the transaction.
Bioavailability is defined as the rate and extent of absorption of a drug from its dosage form and the amount available at the site of action. It depends on pharmaceutical, patient, and route of administration factors. The objectives of bioavailability studies are to develop new formulations, determine the influence of excipients and other drugs, and control drug product quality. Bioavailability can be assessed using pharmacokinetic methods like plasma concentration-time profiles from single and multiple dose studies, and urinary excretion studies. Key parameters analyzed are Cmax, Tmax, and AUC which indicate rate and extent of absorption. Pharmacodynamic methods like acute pharmacological response and therapeutic response studies can also be used when pharmacokinetic methods are not suitable. In
This document discusses bioequivalence and biopharmaceutics. It defines bioequivalence as the same rate and extent of absorption of the active ingredients in two drug products. Bioequivalence studies compare generic drugs to ensure they are biologically equivalent to the branded drug. In vivo and in vitro bioequivalence studies are described, with in vivo requiring human subjects and in vitro using dissolution testing. Factors that can impact bioequivalence like solubility, excipients, and absorption site are outlined.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
ONE COMPARTMENT OPEN MODEL I.V BOLUS (Contact me: dr.m.bharathkumar@gmail.com)DR. METI.BHARATH KUMAR
The document appears to be a scanned receipt from a grocery store listing various food and household items purchased totaling $123.45. It includes the store name, date, time of purchase, payment method (credit card), and signature of the cashier. The receipt provides details of the transaction including item names, quantities, and individual prices.
The document discusses bioavailability studies, which determine the efficiency of drug absorption from different dosage forms and formulations. Key aspects covered include:
- Objectives of bioavailability studies such as determining the influence of excipients and other drugs on absorption during new drug development.
- Factors affecting bioavailability including drug properties, dosage form characteristics, and patient-related factors.
- Methods of measuring bioavailability including plasma concentration-time curves and urinary drug excretion.
- The importance of correlating in vitro dissolution tests to in vivo absorption through levels of in vitro-in vivo correlation (IVIVC).
This document discusses renal and non-renal routes of drug excretion. It describes the key organs and processes involved in excretion, including the nephron in renal excretion and factors that determine if a drug is excreted renally or non-renally. Non-renal excretion includes biliary excretion through the liver and bile ducts. Clearance, excretion ratio, and other pharmacokinetic concepts relating to measurement of excretion are also covered.
This document discusses multicompartment models, including two-compartment models. A two-compartment model classifies body tissues into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues). Depending on the compartment of drug elimination, two-compartment models can describe intravenous bolus administration, intravenous infusion, or extravascular administration. Compartment models are useful for characterizing drug behavior in patients and optimizing dosage regimens.
The document outlines a bioavailability and bioequivalence testing protocol. It begins by defining bioavailability and bioequivalence. It then describes the objectives of bioavailability studies and outlines the key components of a bioavailability study protocol including study design (types of designs discussed are parallel, crossover, Latin square, and balanced incomplete block), subjects, drug administration, sampling, analysis, and statistical analysis. Key aspects of each section are described in detail including considerations for study design, washout periods, single vs. multiple dosing, subject selection, sampling schemes, analysis of biological samples, and use of ANOVA for statistical analysis.
Methods of enhancing Dissolution and bioavailability of poorly soluble drugsRam Kanth
Bioavailability refers to the amount of drug that reaches systemic circulation after administration. It is reduced when drugs are administered orally rather than intravenously due to incomplete absorption and first-pass metabolism. The document discusses several methods for enhancing bioavailability of orally administered drugs with poor solubility or permeability. These include micronization, use of surfactants, salt forms, altering pH, polymorphism, complexation, molecular encapsulation, and forming solid solutions, eutectic mixtures or solid dispersions to improve solubility and dissolution rate.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
The phenomenon of complex formation of drug with protein is called as Protein drug binding. The proteins are particularly responsible for such an interaction. A drug can interact with several tissue components.
This document provides guidelines for conducting bioavailability and bioequivalence studies. It discusses the objectives of such studies, when they are necessary, acceptable study designs, required documentation, and criteria for establishing equivalence between products. The key points covered include:
- The goals of ensuring consistent quality, safety and efficacy of pharmaceuticals.
- Types of studies used, including pharmacokinetic, pharmacodynamic and clinical endpoint trials.
- Standard study designs like randomized crossover trials and considerations for study populations, sampling schedules, and statistical analysis.
- Criteria for waiving BE studies under certain conditions where in vitro dissolution testing can be used instead.
1. The document discusses bioequivalence, which refers to two drug formulations producing comparable levels of the active substance in the bloodstream and providing equivalent therapeutic effects.
2. It defines bioequivalence and outlines the objectives of bioequivalence studies, which are conducted to establish interchangeability between generic and brand-name drugs.
3. The types of bioequivalence studies discussed are in vivo studies, involving human subjects, and in vitro dissolution testing to compare drug release characteristics. Techniques used include blood sampling, analytical methods like HPLC, and statistical tests to determine bioequivalence.
The document discusses bioavailability and bioequivalence studies. It defines bioavailability as the rate and extent of an active drug reaching systemic circulation and being available at its site of action. Bioequivalence refers to comparing the bioavailability of a drug from different formulations. The document outlines the objectives, types of study designs, important considerations like sampling, subjects, and analysis methods for bioavailability and bioequivalence studies.
Bioavailability and bioeqivalance testing PromilaThakur4
Bioavailability is defined as the rate and extent to which an active drug reaches systemic circulation. Objectives of bioavailability studies include developing new formulations and determining the effects of excipients, patient factors, and drug interactions on absorption. Bioavailability can be assessed using pharmacokinetic methods like determining blood concentrations over time to calculate AUC, Cmax, and Tmax, or by measuring urinary drug excretion. Bioequivalence studies establish equivalence between test and reference drug products using randomized crossover or parallel designs in accordance with regulatory guidelines. Key parameters compared include AUC, Cmax, and the time to reach Cmax to ensure bioequivalent drug products have similar rates and extents of absorption.
This document discusses bioavailability and bioequivalence studies. It defines bioavailability as the fraction of a drug that reaches systemic circulation, and bioequivalence as drugs reaching circulation at the same rate and to the same extent. It describes various methods to measure bioavailability including plasma level time studies, urinary excretion studies, and pharmacological or therapeutic response. The document outlines study designs for bioequivalence testing including randomization, cross-over, and Latin square designs. It discusses the importance of these studies for drug development and quality control.
This document discusses bioavailability and bioequivalence of drug products. It defines key terms like bioavailability, bioequivalence, chemical equivalence and absolute/relative bioavailability. It describes objectives of bioavailability studies and methods of measuring bioavailability including pharmacokinetic methods like plasma level time studies and urinary excretion studies, and pharmacodynamic methods like acute pharmacological response and therapeutic response. It also discusses in vitro dissolution studies, IVIVC correlation, types of bioequivalence experimental study designs and statistical interpretation of bioequivalence data.
This document discusses bioavailability and bioequivalence. It defines bioavailability as the rate and amount of drug absorption from its dosage form. Factors that influence bioavailability include pharmaceutical properties, patient factors, and route of administration. Absolute bioavailability compares systemic availability after oral versus intravenous dosing, while relative bioavailability compares oral dosing to an oral standard. Bioequivalence means two products have identical plasma concentration-time profiles without statistical differences. The document outlines methods to measure bioavailability including pharmacokinetic studies using plasma or urine data and pharmacodynamic studies using physiological responses. It also discusses objectives and criteria for bioequivalence studies.
Drug product performance , in vivo: bioavailability and bioequivalenceDipakKumarGupta3
1. Bioavailability studies assess how much of a drug reaches systemic circulation after administration. They are used to define the effects of changes to a drug's formulation or manufacturing process.
2. Key parameters measured include Cmax, Tmax, and AUC, which provide information about a drug's absorption rate and extent. Bioequivalence studies compare these parameters between generic and brand name drugs to ensure equivalent therapeutic effects.
3. Common study designs include single-dose fasting studies, food effect studies, and multiple-dose steady state studies. These follow standard crossover or parallel designs to compare test and reference drug products administered to healthy subjects.
This document discusses bioavailability and bioequivalence studies. It defines bioavailability as the rate and extent of absorption of a drug from its dosage form and defines bioequivalence as two or more identical drug products reaching systemic circulation at the same rate and to the same relative extent. The document outlines various methods to assess bioavailability including plasma level-time studies and urinary excretion studies. It also discusses the objectives and types of bioequivalence studies, including in vivo and in vitro methods.
The document discusses drug product performance and in vivo bioavailability and bioequivalence. It defines bioavailability as the release of a drug substance from a product leading to absorption. Bioavailability studies are used to understand how formulation changes impact pharmacokinetics. They are important for developing new and generic drug products. The document outlines study designs like single-dose fasting studies and food effect studies used to assess bioavailability and establish bioequivalence between products. It also discusses key pharmacokinetic parameters measured in such studies like Cmax, Tmax, and AUC.
Bioavailability & Bioequivalence ppt, Objectives, Improving bioavailability, Assessment of bioavailability, Urinary excretion studies, Blood serum studies, in vitro drug dissolution testing, need for dissolution testing, in vitro drug dissolution testing models, Bioequivalence, Therapeutic equivalence, Types of bioequivalence studies, Pharmacokinetic studies, Methods to enhance dissolution rate.
This document discusses bioequivalence studies, which compare the bioavailability of generic drugs to their branded counterparts. It covers key aspects of study design, including assessing pharmacokinetic parameters like AUC and Cmax in fasting and fed states using single and multiple dose studies. Analytical methods must be validated to measure drug concentrations accurately. Statistical tests like ANOVA are used to determine if generic and branded versions are bioequivalent by having equivalent rates and extents of drug absorption. The goal is to demonstrate generic drugs deliver the same therapeutic effects as the original drug.
Bioavailability is defined as the fraction of an administered drug dose that reaches systemic circulation. It is determined by comparing the rate and extent of absorption of a test formulation to a reference standard, usually an intravenous dose. Key considerations in bioavailability studies include selecting appropriate subjects, study design such as single vs multiple dose studies and washout periods, and ensuring the analytical method can detect drug and metabolite levels. The goal is to understand how formulation characteristics impact the biological performance of the drug.
Bioavailability and bioequivalence are important concepts for regulating generic drugs. Bioavailability refers to the rate and extent that the active drug ingredient is absorbed and available in the body. Bioequivalence means two drug products containing the same active ingredient have the same rate and extent of absorption. For approval, generic drugs must demonstrate bioequivalence to the brand name drug through pharmacokinetic studies comparing metrics like AUC and Cmax between a test and reference drug. The FDA prefers showing bioequivalence through these types of studies using a crossover design in healthy subjects under fasted conditions.
This document provides an overview of bioequivalence and drug product assessment. It defines key terms like bioequivalence and pharmaceutical equivalence. It discusses the need for and types of bioequivalence studies. The document outlines the objectives and statistical evaluation of bioequivalence data. It also describes different study designs like randomized crossover designs and factors to consider like food effects. Furthermore, it discusses the types of evidence required to establish bioequivalence and conditions for biowaivers.
This document provides an introduction to bioequivalence studies, including definitions of key terms, the need for and importance of bioequivalence studies, criteria for establishing a bioequivalence requirement, types of bioequivalence studies, design of bioequivalence studies, evaluation of bioequivalence study results, and clinical significance. It discusses in vivo and in vitro bioequivalence study types and designs, including factors such as single dose, multiple dose, fasting, food effect, and crossover designs. Statistical evaluation methods including ANOVA, confidence intervals, and bioequivalence limits of 80-125% are also summarized.
This document discusses guidelines for bioavailability and bioequivalence studies. It defines key terms like bioavailability, bioequivalence, pharmaceutical equivalents and alternatives. It outlines when bioequivalence studies are necessary, such as for modified release drugs, and when they are not required, such as for parenteral solutions. It also describes the different types of studies including pharmacokinetic, pharmacodynamic and clinical endpoint studies. Finally, it provides details on study design, population, conditions and statistical evaluation for pharmacokinetic bioequivalence studies.
Bioavailability refers to the amount of drug that enters systemic circulation after administration. It is measured using pharmacokinetic methods like plasma concentration-time profiles and urinary excretion studies, or pharmacodynamic methods like measuring physiological responses. Key parameters include AUC, Cmax, Tmax, which provide information on extent and rate of absorption. Absolute bioavailability compares oral and intravenous dosing, while relative bioavailability compares different oral formulations. Multiple dose studies can assess steady-state characteristics. Bioavailability studies are important for drug development and quality control.
Fundamental concept of modified drug releaseAbhinayJha3
Different Terminologies used in a modified release
1. Sustained release
2. Delayed release
3. Prolonged release
4. Extended-release
5. Controlled release
6. Site-specific targeting and receptor targeting
SELECTION OF DRUG CANDIDATE FOR ORAL SUSTAINED RELEASE SYSTEMS, BIOPHARMACEUTICAL CLASSIFICATION SYSTEM.
This document provides an introduction to biopharmaceutics. It defines biopharmaceutics as the study of how the physicochemical properties of drugs and dosage forms affect drug absorption rates and levels. Key factors discussed include drug protection/stability, release rates, dissolution rates, and availability at the site of action. The document also discusses the significance of biopharmaceutics studies in understanding relationships between physical/chemical drug properties, dosage forms, administration routes, and systemic drug absorption levels and therapeutic effects.
This document provides an overview of pharmacokinetics, including definitions, compartment models, non-compartment models, physiological models, and a one-compartment open model. Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of drugs in the body. Compartmental models represent the body as a series of compartments and use rate constants to describe drug movement between compartments. A one-compartment open model can be used to model intravenous bolus administration, where drug is eliminated from the body via first-order kinetics.
Nonlinear pharmacokinetics occurs when the body's processing of a drug is saturated at higher doses, causing kinetics parameters like clearance and half-life to change with dose. Michaelis-Menten kinetics are commonly used to model nonlinear metabolism, where the metabolic rate approaches a maximum (Vmax) at high concentrations. Parameters like Vmax and KM can be estimated from steady-state dosing and concentration data by linearizing the Michaelis-Menten equation. Drugs like phenytoin exhibit nonlinear kinetics due to capacity-limited hepatic metabolism.
This document discusses drug elimination, which involves biotransformation (metabolism) and excretion of drugs from the body. It describes zero-order and first-order elimination kinetics, drug metabolism pathways including phase I and II reactions, and factors that influence renal excretion of drugs such as physicochemical properties and plasma concentration. Renal clearance is defined as the volume of plasma cleared of drug per unit time by the kidneys. Non-renal routes of excretion include biliary, pulmonary, dermal and gastrointestinal excretion.
This document discusses drug distribution, including tissue permeability, compartments for drug storage, plasma protein binding, kinetics of protein binding, factors affecting binding, and clinical significance. It notes that distribution is driven by concentration gradients and is not uniform across tissues. It also discusses redistribution between compartments over time. Protein binding influences absorption, distribution, metabolism, elimination and effects of drugs.
This document discusses drug absorption, including definitions, mechanisms, and factors influencing absorption. It covers three main mechanisms of absorption - transcellular, paracellular, and endocytosis. Pharmaceutical factors like solubility and dosage forms as well as patient factors like age, disease states, and gastrointestinal contents can impact drug absorption. Non-oral routes of administration like buccal, rectal, pulmonary provide advantages over oral routes by bypassing the gastrointestinal tract and liver metabolism, allowing for more rapid and complete drug absorption.
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ISO/IEC 27001, ISO/IEC 42001, and GDPR: Best Practices for Implementation and...PECB
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Date: May 29, 2024
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2. Contents
• Bioavailability and Bioequivalence: Introduction
• Definition and Objectives of bioavailability,
• Bioavailability Study Designs
• Absolute and Relative Bioavailability
• Measurement of bioavailability,
• In-vitro drug Dissolution models,
• In-vitro-in-vivo correlations,
• Bioequivalence studies,
• Methods to enhance the dissolution rates and
bioavailability of poorly soluble drugs.
3. Bioavailability and
Bioequivalence: Introduction
• The extent and the rate of drug absorption play an
important role in pharmacokinetics, and this
parameters are usually referred as the drug
bioavailability.
• For example, a fraction of the dose may be
metabolized during the early passage through the
gastrointestinal tract or through the liver after an oral
dose, or part of the dose may not reach the blood due
to drug malabsorption.
• The consequence is an incomplete absorption of the
drug into the systemic circulation and an incomplete
drug availability may produce ineffectiveness of the
treatment.
4. Bioavailability and
Bioequivalence: Introduction
DIFFERENCE BETWEEN BIOAVAILABILITY AND BIOEQUIVALENCE
• Bioavailability
– 1. The rate and extent of drug absorption of unchanged drug from its dosage
form into the systemic circulation.
– 2. Measured by the demonstrated bioequivalence studies of reference
protocol.
– 3. Bioavailability is a comparison of the drug product to an IV formulation.
– 4. This studies are expletory
– 5. Evaluate geometric ratio but don’t test a statistical hypothesis
– 6. Not require a similar time to achieve peak blood concentrations.
– 7. Provide indirect information regarding the pre-systemic and systemic
metabolism of the drug
– 8. Determined only which active ingredient or moiety become available in the
site of action.
– 9. Provide useful information to establish dosage regimens and to support
drug labeling, such as distribution and elimination characteristics of the drug
– 10. For example, if 100 mg of a drug are administered orally and 70 mg of this
drug are absorbed unchanged, the bioavailability is 0.7 or 70%
5. Bioavailability and
Bioequivalence: Introduction
• Bioequivalence
– 1. Two or more similar dosage forms reach the systemic circulation at the
same relative rate and extent.
– 2. Bioequivalence has been established via bioavailability testing.
– 3. Bioequivalence is a comparison with predetermined bioequivalence limits.
– 4. This studies are confirmatory .
– 5. Test a statistical hypothesis by evaluating geometric ratio.
– 6. Require similar times to achieve peak blood concentrations.
– 7. Provide a link between the pivotal and early clinical trial formulation.
– 8. Determined the therapeutic equivalence between the pharmaceutical
equivalence generic drug product and a corresponding reference listed drug.
– 9. Provide information on product quality and performance when there are
changes in components, composition and method of manufacture after
approval of the drug product.
– 10. Example- a receptor in the brain - the brand name and the generic drug
should deliver the same amount of active ingredient to the target site.
6. Objectives of Bioavailability
studies
• Bioavailability studies are important in the –
– 1. Primary stages of development of a suitable dosage
form for a new drug entity to obtain evidence of its
therapeutic utility.
– 2. Determination of influence of
• - excipients,
• - patient related factors,
• - possible interaction with other drugs on the efficiency of
absorption.
– 3 Development of new formulations of the existing
drugs.
7. Objectives of Bioavailability
studies
– 4. Control of quality of a drug product during the
early stages of marketing in order to determine
the influence of processing factors, storage and
stability on drug absorption.
– 5. Comparison of availability of a drug substance
from different dosage forms or form the same
dosage form produced by different manufacturers.
8. Significance of Bioavailability
• Significance of Bioavailability
– Drugs having low therapeutic index, e.g. cardiac
glycosides, quinidine, phenytoin etc. and narrow
margin of safety e.g. antiarrythmics, antidiabetics,
adrenal steroids, theophylline .
– Drugs whose peak levels are required for the effect of
drugs, e.g. phenytoin, phenobarbitone, primidone,
sodium valporate, antihypertensives, antidiabetics
and antibiotics.
– Drugs that are absorbed by an active transport, e.g.
amino acid analogues, purine analogues etc. In
addition, any new formulation has to be tested for its
bioavailability profile.
9. Significance of Bioavailability
• Drugs which are disintegrated in the alimentary canal
and liver, e.g.chlorpromazine etc. or those which under
go first pass metabolism.
• Formulations that give sustained release of drug,
formulations with smaller disintegration time than
dissolution rate and drugs used as replacement therapy
also warrant bioavailability testing.
• Drugs with steep dose response relationship i.e. drugs
obeying zero order kinetics / mixed order elimination
kinetics ( e.g. warfarin , phenytoin, digoxin, aspirin at
high doses, phenylbutazone)
10. Bioavailability Study Designs
• Absolute Bioavailability ( F ) vs Relative
Bioavailability:
– “When the systemic availability of a drug administered
orally is determined in comparison to its intravenous
administration ,is called as absolute bioavailability”.
– Its determination is used to characterize a drug’s
inherent absorption properties from the e.v. Site.
11. Bioavailability Study Designs
• Relative Bioavailability ( Fr )
– “When the systemic availability of the drug after
oral administration is compared with that of oral
standard of same drug ( such as aqueous or non
aqueous solution or a suspension ) is referred as
Relative Bioavailability or comparative ”.
– e.g. comparison between cap. Amox and susp.
Amox
– It is used to characterize absorption of a drug from
its formulation. It is denoted by symbol Fr.
Fr = AUC A / AUC B
12. Bioavailability Study Designs
Single Dose vs Multiple Dose Studies
• Single dose study
– Advantages
• More common
• Easy
• less tedious
• Less exposure to drug.
– Disadvantages
• Difficult to predict steady state characteristics.
13. Bioavailability Study Designs
Multiple dose study
• Advantages
– Accurate.
– Easy to predict the peak & valley characteristics of drug.
– Few blood samples required.
– Ethical. And Small inter subject variability .
– Better evaluation of controlled release formulations.
– Can detect non linearity in pharmacokinetics.
– Higher blood levels ( d/t cumulative effect ).
– Eliminates the need for long wash out period between doses.
• Disadvantages
– Poor subject compliance.
– Tedious , time consuming.
– More drug exposure.
– More difficult and costly.
14. Bioavailability Study Designs
• Human Voluntiers: Healthy vs Patients
– Patients :
• used in multiple dose studies.
• Advantages
– 1. Patient gets benefited from the study.
– 2. Reflects better therapeutic efficacy.
– 3. Drug absorption pattern in disease states evaluated.
– 4. Avoids ethical quandary.
• Disadvantages
– 1. Disease states , other drugs affects study
– 2. Difficult to follow stringent study conditions.
15. Bioavailability Study Designs
• Healthy human volunteers
– i. Young
– ii. Healthy
– iii. Male ( females : e.g. OC pills study )
– iv. Body wt. within narrow range.
– v. Restricted dietary & fixed activity conditions.
19. In-vitro drug Dissolution models
Types Of Dissolution Models
• 1 Diffusion layer model
• 2 Danckwert’s model
• 3 Interfacial barrier model
• 4 Zero order model
• 5 First order model
• 6 Higuchi model
• 7 Korsmeyer- Peppas model
• 8 Hixson – Crowell model
• 9 Baker- Lonsdale model
• 10 Weibull model
20. In-vitro drug Dissolution models
1. Diffusion layer model
It is a simplest model where dissolution of crystal, immersed in liquid takes place
without involving reactive or electrical forces. Consist of two consecutive
steps:
1. Solution of the solid to form a thin film or layer at the solid / liquid
interface called as stagnant film or diffusion layer which is saturated with the
drug this step is usually rapid (instantaneous).
2. Diffusion of the soluble solute from the stagnant layer to the bulk of the
solution this step is slower and is therefore the rate determining step in the
drug dissolution.
21. In-vitro drug Dissolution models
• Using Fick’s law, Noyes- Whitney equation for diffusion layer model
is as follows:
Where,
dc/dt = dissolution rate of the drug
D = diffusion coefficient of the drug
A = surface area of the dissolving solid
Kw/o = water/oil partition coefficient of the drug
V = volume of dissolution medium
h = thickness of the stagnant layer
(Cs-Cb) = concentration gradient of diffusion of drug
22. In-vitro drug Dissolution models
2. Danckwert’s model
• This theory assumes that solid-solution equilibrium is achieved at
interface and mass transport is slow step in dissolution process.
• The model could be visualized as a very thin film having a conc. Ci
which is less than saturation, as it is constantly being exposed to
fresh surfaces of liquid having a conc. much less than Ci.
23. In-vitro drug Dissolution models
• Acc. to model, the agitated fluid consist of mass of eddies or packets that
are continuously being exposed to new surfaces of solid and then carried
back to bulk of liquid.
• Diffusion occurs into each of these packets during short time in which the
packet is in contact with surface of solid. Since turbulence actually extends
to surface, there is no laminar boundary layer and so no stagnant film
exists. Instead, surface continually being replaced with fresh liquid.
• The Danckwert’s model can be expressed by the following equation,
• where, m = mass of solid dissolved y = rate of surface renewal
24. In-vitro drug Dissolution models
• 3. Interfacial Barrier model
– Interfacial barrier model considers drug dissolution as crystal
dissolution wherein solids get hydrated initially and is not
instantaneous.
– In this model it is assumed that the reaction at solid surface is not
instantaneous i.e. the reaction at solid surface and its diffusion across
the interface is slower than diffusion across liquid film.
– Therefore the rate of solubility of solid in liquid film becomes the rate
limiting than the diffusion of dissolved molecules .
25. In-vitro drug Dissolution models
– When considering the dissolution of crystal will
have a different interfacial barrier given by the
following equation,
dm/dt = Ki (Cs – C)
– where, Ki = effective interfacial transport constant
26. In-vitro drug Dissolution models
4. Zero order model
– Dissolution of the drug from pharmaceutical
dosage forms that do not disaggregate and release
the drug slowly can be represented by the
following equation:
Wo – Wt = Kt
– Where, Wo = the initial amount of drug in the
pharmaceutical dosage form Wt = the amount of
drug in the pharmaceutical dosage form at time t
and K is proportionality constant
27. In-vitro drug Dissolution models
– The pharmaceutical dosage forms following this
profile release the same amount of drug by unit of
time and it is the ideal method of drug release in
order to achieve a pharmacological prolonged action.
The following relation can, in a simple way, express
this model:
Qt = Q0 + K0t
Where, Qt = the amount of drug dissolved in time t, Q0 = the initial
amount of drug in the solution and Ko = the zero order release
constant. To study the release kinetics, data obtained from in
vitro drug release studies were plotted as cumulative amount of
drug released versus time.
28. In-vitro drug Dissolution models
• Drug release rate - Independent of concentration
• Graphical representation - %CDR Vs Time and straight line is
obtained
29. In-vitro drug Dissolution models
• 5. First order model
– The application of this model to drug dissolution studies was first
proposed by Gibaldi and Feldman (1967) and later by Wagner (1969).
– This model has been also used to describe absorption and/or
elimination of some drugs, although it is difficult to conceptualize this
mechanism in a theoretical basis The dissolution phenomena of a solid
particle in a liquid media imply a surface action, as can be seen by the
Noyes–Whitney Equation:
dc/dt = K (Cs - C)
Where C is the concentration of the solute in time t, Cs is s order the solubility
in the equilibrium at experience temperature and K is first order
proportionality constant.
30. In-vitro drug Dissolution models
– The plot between time (hrs) Vs log cummulative % of
drug remaining to be release gives a straight line
– Application: This relationship can be used to describe
the drug dissolution in pharmaceutical dosage forms
such as those containing water soluble drugs in
porous matrices .
31. In-vitro drug Dissolution models
6. Higuchi Model
• This is the first mathematical model that describes drug
release from a matrix system, proposed by Higuchi in 1961 .
• This model is based on different hypothesis that,
– Initial drug concentration in the matrix is much higher than drug
solubility,
– Drug diffusion takes place only in one dimension (Edge effect
should be avoided),
– Drug particles are much smaller than thickness of system,
– swelling of matrix and dissolution are less or negligible,
– Drug diffusivity is constant,
– Perfect sink condition are always attained in the release
environment.
32. In-vitro drug Dissolution models
• The study of dissolution from a planar system
having a homogeneous matrix can be obtained by
the equation:
A=[D(2C-Cs)Cs X t]1/2
Where, A = amount of drug released in time ‘t’ per unit
area
D = diffusivity of drug molecule in the matrix substance
C = initial drug concentration
Cs = drug solubility in the matrix media.
33. In-vitro drug Dissolution models
• The following graph shows the drug release through Higuchi Model,
• Application : This relationship can be used to describe the drug
dissolution from several types of modified release pharmaceutical
dosage forms, as in the case of some transdermal systems and
matrix tablets with water soluble drugs.
34. In-vitro drug Dissolution models
7. Hixson-Crowell Model
• Drug powder that having uniformed size particles,
Hixson and Crowell derived the equation which
expresses rate of dissolution based on cube root of
weight of particles and the radius of particle is not
assumed to be constant.
• This is expressed by the equation,
Mo1/3 - Mt1/3 = κ t
• Where, Mo = the initial amount of drug in the
pharmaceutical dosage form, Mt =remaining amount
of drug in the pharmaceutical dosage form at time ‘t’
and κ is proportionality constant
35. In-vitro drug Dissolution models
• The plotted graph will be linear if the following conditions are fulfilled,
• The equilibrium condition are not reached and
• The geometrical shape of the pharmaceutical dosage form diminished
proportionally over time.
• Applications: This relationship can be used to describe the drug
dissolution from several types of modified release pharmaceutical dosage
forms, as in the case of some transdermal systems and matrix tablets with
water soluble drugs
36. In-vitro drug Dissolution models
• 8. Korsemeyer- Peppas model
– Korsemeyer (1983) derived a simple relationship which
described drug release from a polymeric system equation.
– To find out the mechanism of drug release, first 60% drug
release data were fitted in Korsmeyer -Peppas model.
– The Korsemeyer –Peppas empirical expression relates the
function of time for diffusion controlled mechanism.
– It is given by the equation,
Mt / M∞ = Ktn
– Where, Mt / M∞ is a fraction of drug released t = time k =
release rate constant includes structural and geometrical
characteristic of the dosage form
37. In-vitro drug Dissolution models
– n = release component which is indicative of the drug
release mechanism.
– where, n is diffusion exponent
• if n = 1, the release is zero order
• if n= 0.5 the release is best described by Fickian diffusion
• Application: This equation has been used to the linearization of
release data from several formulations of microcapsules or
microspheres
38. In-vitro drug Dissolution models
• 9. Baker- Lonsdale model
– This model was developed by Baker and Lonsdale
(1974) from the Higuchi model and described the drug
release from spherical matrices by using the equation:
f1= 3/2[1-(1-Ct/C∞)2/3+ Ct/C∞ = (3DmCms)/(ro2Co)X t
– Where, At = drug released amount at time t A∞ =
amount of drug released at an infinite time, Dm =
diffusion coefficient, Cms = drug solubility in the
matrix, ro = radius of the spherical matrix Co = initial
concentration of drug in the matrix
39. In-vitro drug Dissolution models
• To study the release kinetics, data obtained
from in vitro drug release studies were plotted
as *d (At / A∞)+ / dt with respect to the root of
time inverse. Application:
• This equation has been used to the
linearization of release data from several
formulations of microcapsules or
microspheres.
40. In-vitro drug Dissolution models
• 10. Wiebull Model
– Wiebull model is generally applied to drug dissolution
or release from pharmaceutical dosage forms These
accumulated fraction of drug M in solution at time t is
given by Wiebull equation,
M= Mo[1-e-(t-T/a)b]
– Where, m = % dissolved in time ‘t’ a= scale parameter
which defines the time scale of the dissolution
process Ti = lag time( generally zero) b = shape factor
41. In-vitro drug Dissolution models
– This equation can be widely used for analysis and
characterisation Of of Drug Dissolution process
from different dosage form.
– The kinetic model that best fits the dissolution
data is evaluated by comparing the correlation
coefficient(r) values obtained in various models.
42. In-vitro drug Dissolution models
Applications of Dissolution models:
• 1. Product Development Important tool during
development of dosage form.
• 2. Quality Assurance: D.T. performed on future
production lots and is used to assess the lot-tolot
performance characteristics of drug product and
provide continued assurance of product
integrity/similarity.
• 3. Product Stability: In-vitro dissolution also used
to assess drug product quality with respect to
stability and shelf- life.
43. In-vitro drug Dissolution models
• 4. Comparability Assessment : Also useful for assessing
the impact of pre- or postapproval changes to drug
product such as changes to formulation or
manufacturing process. Thus, in-vitro comparability
assessment is critical to ensure continued performance
equivalency and product similarity.
• 5. Waivers of in-vivo bioequivalence requirements: In-
vitro dissolution testing or drug release testing may be
used for seeking waiver of required product to conduct
in-vivo bioavailability or bioequivalence studies
44. In-vitro-in-vivo correlations
• An in vitro in vivo correlation (IVIVC) is a
predictive mathematical model that describes
the relationship between an in vitro property
of a dosage form (primarily dissolution or drug
release) and a relevant in vivo response
(primarily a drug's plasma concentration or
the amount of drug absorbed)
45. In-vitro-in-vivo correlations
• IVIVC could also be employed to establish dissolution specifications and
to support and/or validate the use of :
– Dissolution methods
– Quality control procedures
– Tablet or Capsule disintegration
– Instrumental methods of analysis
– Dissolution Rate Test
– The rate of drug absorption
– Dissolution Profile Parameters
– In Vivo Performance
– Proper In-Vitro Dissolution Rate
– Correlate the data with the bioavailability
• Important Purpose:
– 1. Providing necessary process control
– 2. Determing stability of dosage form ANUSHA NADIKATLA
47. Bioequivalence studies
• It refers to the drug substance in two or more identical dosage
forms, reaches systemic circulation at the same rate and to the
same relative extent.
• i.e. their plasma concentration-time profiles will be identical
without significant statistical differences.
• Advantages:
– Minimizes the effect of inter subject variability.
– It minimizes the carry over effect.
– Requires less number of subjects to get meaningful results.
• Disadvantages:
– Requires longer time to complete the studies.
– Completion of studies depends on number of formulations evaluated
in the studies.
– Increase in study period leads to high subject dropouts.
– Medical ethics does not allow too many trials on a subject
continuously for a longer time.
48. Bioequivalence studies
Requirements/Objectives:
• If a new product is intended to be a substitute for an
approved medicinal product as a pharmaceutical
equivalent or alternative,the equivalence with this
product should be shown or justified.
• In order to ensure clinical performance of such drug
products,bioequivalence studies should be performed.
Bioequivalence studies are conducted if there is:
• A risk of bio - inequivalence and/or
• A risk of pharmacotherapeutic failure or diminished
clinical safety.
49. Bioequivalence studies
• There are several types of equivalences.
– A. Chemical Equivalence
– B. Pharmaceutical Equivalence
– C. Bioequivalence
– D. Therapeutic Equivalence
• A. Chemical Equivalence :-
– It indicates that two or more drug products contain the same
labelled chemical substance as an active ingredient in the same
amount.
• B. Pharmaceutical Equivalence :-
– This term implies that two or more drug products are identical
in strength, quality, purity, content uniformity and disintegration
and dissolution characteristics. They may, however, differ in
containing different excipients.
50. Bioequivalence studies
• C. Bioequivalence :-
– It is a relative term which denotes that the drug substance
in two or more identical dosage forms, reaches the
systemic circulation at the same relative rate and to the
same relative extent i.e. their plasma concentration-time
profiles will be identical without significant statistical
differences.
– When statistically significant differences are observed in
the bioavailability of two or more drug products,
bioinequivalence is indicated.
• D. Therapeutic Equivalence :-
– This term indicates that two or more drug products that
contain the same therapeutically active ingredient elicit
identical pharmacological effects and can control the
disease to the same extent.
51. Bioequivalence studies
• Bioequivalence can be demonstrated either –
• In vivo, or In vitro
In-vivo
• The following sequence of criteria is useful in assessing
the need for in vivo studies:
– 1. Oral immediate-release products with systemic action-
– Indicated for serious conditions requiring assured response.
– Narrow therapeutic margin.
– Pharmacokinetics complicated by absorption < 70 % or absorption
window, nonlinear kinetics, presystemic elimination > 70 %.
– Unfavorable physiochemical properties, e.g. low solubility, metastable
modification, instability, etc.
– Documented evidence for bioavailability problems. No relevant data
available, unless justification by applicant that in vivo study is not
necessary
52. Bioequivalence studies
– 2. Non-oral immediate-release products.
– 3. Modified-release products with systemic action.
• In vivo bioequivalence studies are conducted in the usual
manner as discussed for bioavailability studies, i.e. the
pharmacokinetic and the pharmacodynamic methods.
• 1. Pharmacokinetic Methods
– a) Plasma level-time studies
– b) Urinary Excretion studies
• 2. Pharmacodynamic Methods
– a) Acute pharmacological response
– b) Therapeutic response
53. Methods to enhance the dissolution rates and
bioavailability of poorly soluble drugs.
• 1)Particle Size Reduction
– Conventional methods
– Micronization
– Nanosuspension
• 2)Hydrotropy
• 3)Cosolvency
• 4)Solubilization by Surfactants
• 5)Solid Dispersion
– The fusion (melt) method
– The solvent method
– Dropping method
• 6)pH adjustment
• 7)High Pressure Homogenization
• 8) Supercritical fluid recrystallization(SCF)
• 9) Sonocrystallisation
54. Methods to enhance the dissolution rates and
bioavailability of poorly soluble drugs.
• 10) Complexation
– Physical Mixture
– Kneading method
– Co-precipitate method
• 11) Spray Drying
• 12)Inclusion Complex Formation-Based Techniques
– Kneading Method
– Lyophilization/Freeze-Drying Technique
– Microwave Irradiation Method
• 13) Liquisolid technique
• 14) Micro-emulsion
• 15) Self-Emulsifying Drug Delivery Systems
• 16) Neutralization 17)Cryogenic Method
– Spray Freezing onto Cryogenic Fluids
– Spray Freezing into Cryogenic Liquids (SFL)
– Spray Freezing into Vapor over Liquid (SFV/L)
– Ultra-Rapid Freezing (URF) 18)Polymeric Alteration
• 19) Salt formation
55. References
• Brahmankar, “A textbook of Bio pharmaceutics and
Pharmacokinetic”, 3 rd edition, page no.15-48.
• https://www.researchgate.net/post/What_is_the_difference_betw
een_bioavailability_and_bioequivalence
• https://www.slideshare.net/prajaktachavan7902/solubility-
enhancement-by-using-various-techniques
• https://www.slideshare.net/ANUSHANADIKATLA/in-vitro-in-vivo-
correlation-122984972
• https://www.slideshare.net/sujitpatel11/bioequivalence-studies
• Remington’s “ The science and practice of pharmacy”, 21st edition,
page no. 672-685
• C.V.S. Subrahmanyam, ”Textbook of Physical Pharmaceutics”, 2nd
edition, Vallabh Prakashan, page no. 85-109