This presentation gives a bird's eye view on Dissolution in context with IVIVC. It discusses various levels of Correlations currently in practice. IVIVC are explained in light of biowaivers It also touches upon IVIVR, IVIVM etc.
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".
The document discusses invitro dissolution testing. It begins with an introduction to dissolution and BCS classification. It then covers theories of dissolution like the diffusion layer model. It describes various invitro dissolution test models including non-sink methods like the USP rotating basket and paddle apparatus and sink methods like the flow through column method. Finally, it discusses factors that can affect dissolution testing and provides a conclusion.
1. Dissolution is the process by which a solid substance dissolves in a solvent to form a solution. The rate of dissolution depends on factors like temperature, solvent composition, and the liquid/solid interface area.
2. There are several theories that describe the drug dissolution process, including the diffusion layer model, penetration or surface renewal theory, and interfacial barrier model. The most common model is the diffusion layer model, which involves the formation of a saturated film at the solid/liquid interface and diffusion of the drug through this layer.
3. Key factors that affect drug dissolution include the solubility and permeability of the drug substance, the pH and volume of the dissolution medium, and the design of
This document discusses various study designs used in bioequivalence studies. It describes the objectives of such studies as determining if a test product is bioequivalent to a reference product when administered at the same molar dose under similar conditions. Some key study designs discussed include non-replicated parallel studies for long-acting drugs, multiple dose steady state studies, and clinical endpoint studies comparing therapeutic effects. Special considerations are also noted for highly variable drugs.
CLINICAL SIGNIFICANCE OF BIOEQUIVALENCE STUDIES, BIOEQUIVALENCE, REASONS TO PERFORM BIOEQUIVALENCE STUDIES , NEED FOR BIOEQUIVALENCE STUDIES, IMPORTANCE OF BIOEQUIVALANCE STUDIES, DETERMINATION OF BIOEQUIVALENCE OF A DRUG PRODUCT, CLINICAL SIGNIFICANCE.
Preparation & stability of large & small volume parentralsROHIT
This document discusses parenteral formulations, including definitions, advantages, disadvantages, and classifications. It provides details on the preparation of small volume parenterals and large volume parenterals, including vehicles, buffers, preservatives, and other excipients used. It also covers the stability considerations for parenteral formulations and factors that influence syringeability, injectability, clogging, drainage, resuspendibility, and sedimentation of suspensions.
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.
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".
The document discusses invitro dissolution testing. It begins with an introduction to dissolution and BCS classification. It then covers theories of dissolution like the diffusion layer model. It describes various invitro dissolution test models including non-sink methods like the USP rotating basket and paddle apparatus and sink methods like the flow through column method. Finally, it discusses factors that can affect dissolution testing and provides a conclusion.
1. Dissolution is the process by which a solid substance dissolves in a solvent to form a solution. The rate of dissolution depends on factors like temperature, solvent composition, and the liquid/solid interface area.
2. There are several theories that describe the drug dissolution process, including the diffusion layer model, penetration or surface renewal theory, and interfacial barrier model. The most common model is the diffusion layer model, which involves the formation of a saturated film at the solid/liquid interface and diffusion of the drug through this layer.
3. Key factors that affect drug dissolution include the solubility and permeability of the drug substance, the pH and volume of the dissolution medium, and the design of
This document discusses various study designs used in bioequivalence studies. It describes the objectives of such studies as determining if a test product is bioequivalent to a reference product when administered at the same molar dose under similar conditions. Some key study designs discussed include non-replicated parallel studies for long-acting drugs, multiple dose steady state studies, and clinical endpoint studies comparing therapeutic effects. Special considerations are also noted for highly variable drugs.
CLINICAL SIGNIFICANCE OF BIOEQUIVALENCE STUDIES, BIOEQUIVALENCE, REASONS TO PERFORM BIOEQUIVALENCE STUDIES , NEED FOR BIOEQUIVALENCE STUDIES, IMPORTANCE OF BIOEQUIVALANCE STUDIES, DETERMINATION OF BIOEQUIVALENCE OF A DRUG PRODUCT, CLINICAL SIGNIFICANCE.
Preparation & stability of large & small volume parentralsROHIT
This document discusses parenteral formulations, including definitions, advantages, disadvantages, and classifications. It provides details on the preparation of small volume parenterals and large volume parenterals, including vehicles, buffers, preservatives, and other excipients used. It also covers the stability considerations for parenteral formulations and factors that influence syringeability, injectability, clogging, drainage, resuspendibility, and sedimentation of suspensions.
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.
This document discusses bioequivalence studies. It begins with an introduction and objectives. It then defines bioequivalence according to the FDA and WHO as the rates and extents of active ingredients being available between two products. It discusses the need for bioequivalence studies for generic approval and reasons for in vivo studies. It also covers study designs, types of evidence to establish bioequivalence, statistical evaluation of data, and biowaivers. The overall purpose is to ensure generic drugs are equivalent to their brand name counterparts in performance.
Properties of GI tract, pH partition hypothesis Naveen Reddy
Drug absorption from the gastrointestinal (GI) tract depends on several physiological factors:
1) Gastric emptying and intestinal transit time influence drug absorption by determining how long drugs remain in areas where absorption can occur. Faster emptying and transit generally increase absorption rate.
2) Water fluxes in the GI tract can impact drug dissolution and movement within the lumen, affecting absorption. Considerable water is secreted in the small intestine and mostly reabsorbed.
3) The permeability of drugs is affected by their solubility, ionization state, and lipophilicity, which determine how well drugs can pass through membranes according to the pH partition hypothesis. However, the microclimate pH at the membrane surface can differ
Rate limiting steps in drug absorption [autosaved]Nagaraju Ravouru
Rate limiting steps in drug absorption 1.Disintegration time
2.Dissolution and solubility
3.Physical and chemical nature of active drug substance
4.Nature of excipients
5.Method of granulation
6.Dissolution test conditions
7.Gastric emptying
study design for bioavailability and bioequivalencePriya Rajput
Bioavailability is the fraction of an administered dose of a drug that reaches systemic circulation. It is 100% for intravenous administration but generally decreases for other routes due to incomplete absorption and first-pass metabolism. There are two types of bioavailability - absolute and relative. Bioequivalence assesses the expected in vivo biological equivalence of two drug preparations and is determined when there is no more than 20% difference in AUC and Cmax between formulations. In vivo bioequivalence studies involve pharmacokinetic and pharmacodynamic methods to measure these parameters from plasma and urine data.
The document discusses comparison of dissolution profiles through different methods and establishing an IVIVC (in vitro-in vivo correlation). It provides definitions of dissolution profile and objectives of comparing profiles. Various methods for comparing profiles are described, including graphical, statistical, and model-dependent/independent methods. Key factors for determining similarity between dissolution profiles using statistical methods like difference factor and similarity factor are outlined. The importance of developing an IVIVC to reduce costs and the need for bioavailability studies is also mentioned. A research article comparing different brands of metformin tablets using tests like dissolution rate, drug content and disintegration is briefly summarized.
The document discusses the Biopharmaceutics Classification System (BCS), which is a framework developed by the FDA to classify drugs based on their aqueous solubility and intestinal permeability. The BCS aims to improve drug development and review processes by identifying when clinical bioequivalence tests are not necessary. It classifies drugs as Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability) or Class IV (low solubility, low permeability) based on their solubility and permeability parameters. The classification can help determine if in vitro dissolution tests alone can demonstrate bioequivalence or if in vivo testing is still required.
The three main rate limiting steps in drug absorption from oral solid dosage forms are disintegration, dissolution, and gastric emptying. Disintegration involves the breakdown of the solid dosage form into smaller particles so that the drug can be released. Dissolution is the process by which the drug becomes dissolved in water to be absorbed. Gastric emptying determines how quickly the drug formulation moves from the stomach into the intestines, where most absorption occurs. Several drug and formulation properties can impact these steps and influence overall drug absorption.
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 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.
Methods For Assesment Of Bioavailability Anindya Jana
This document summarizes a seminar presentation on methods for determining bioavailability. It defines bioavailability as the rate and extent to which the active substance of a drug is absorbed and available at the site of action. It then describes the main objectives of bioavailability studies which include aiding new drug and formulation development. The key methods discussed for assessing bioavailability include measuring plasma drug concentration, urinary drug excretion, acute pharmacodynamic effects, clinical observations, and in vitro drug dissolution studies. Specific parameters are defined for each method such as Cmax, AUC, tmax, Du, and Emax. Finally, the document summarizes two literature articles that developed formulations to enhance the oral bioavailability of curcumin and edarav
it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.
The document discusses the pH partition hypothesis, which states that the absorption of drugs across biomembranes is governed by the drug's dissociation constant (pKa), lipid solubility of the un-ionized form, and the pH of the absorption site. According to the hypothesis, only the un-ionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its un-ionized form can be calculated using the Henderson-Hasselbach equation based on the drug's pKa and the pH. However, the pH partition theory is an oversimplification and does not always accurately predict drug absorption behavior.
This document discusses drug product performance and bioequivalence studies. It defines drug product performance as the release of the drug substance from the product leading to bioavailability, which relates to clinical safety and efficacy. Bioequivalence studies compare formulations and are used to assess the impact of changes to the drug substance, formulation, or manufacturing process. They can be conducted in vivo using pharmacokinetic or pharmacodynamic endpoints or in vitro using dissolution studies.
permeation enhancers by Hemant Chalaune ist M pharm Gaule Jeevan
This document discusses skin as a drug delivery route and permeation enhancers. It begins with an overview of skin structure and properties that create a barrier to drug delivery. It then discusses permeation enhancers, classifying them as chemical or physical and describing examples from each class. The document explains several specific permeation enhancers in depth, including their proposed mechanisms of action, such as disrupting lipid packing or increasing hydration. It concludes that permeation enhancers are crucial components for improving drug bioavailability through the skin.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
This document discusses methods for comparing drug dissolution profiles, which provide information about how completely and quickly an active pharmaceutical ingredient is released from its dosage form. Graphical and statistical methods are described for directly comparing dissolution curves. Model-dependent approaches apply kinetic models like zero-order, first-order, and Higuchi models to the data. Model-independent methods calculate similarity factors f1 and f2 that provide single values for comparing profiles. Comparing dissolution profiles is important for evaluating drug release and bioequivalence of pharmaceutical formulations.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
The document provides an overview of drug dissolution including:
- Definitions of dissolution rate and intrinsic dissolution rate.
- Theories of drug dissolution including the diffusion layer model, Danckwert's model, and the interfacial barrier model.
- Factors that affect drug dissolution related to the physicochemical properties of drugs, drug product formulation, processing factors, dissolution apparatus and test parameters.
- Importance and applications of drug dissolution testing in product development, quality assurance, stability assessment, and biowaivers.
The document discusses various dissolution models that describe drug release from pharmaceutical dosage forms. It begins by defining dissolution and explaining the need for dissolution models. It then describes several common dissolution models - the diffusion layer model, Dankwaet's model, interfacial barrier model, Higuchi model, Korsemeyer-Peppas model, and Baker-Lonsdale model. Each model makes different assumptions about the drug release mechanisms and can be used to analyze dissolution data using mathematical equations. In conclusion, dissolution models provide a quantitative way to interpret dissolution results and describe drug release profiles.
In-vitro in vivo dissolution correlation BCS classificationRoshan Bodhe
The document discusses in vitro in vivo correlation (IVIVC) and the Biopharmaceutical Classification System (BCS). It introduces the BCS, which classifies drugs based on their solubility and permeability. Drugs fall into four classes based on these properties, with Class I drugs being highly soluble and permeable. The document discusses factors that determine drug absorption like solubility, permeability, and dissolution. It describes methods to determine these properties and outlines the common dissolution apparatus and factors affecting dissolution testing. The goals of BCS and examples of drugs in each class are also provided.
The document provides an overview of the Biopharmaceutics Classification System (BCS). The BCS classifies drugs into four classes based on their aqueous solubility and permeability characteristics. Class I drugs are highly soluble and permeable. Class II drugs are highly permeable but poorly soluble. Class III drugs are highly soluble but poorly permeable. Class IV drugs exhibit low solubility and permeability. The BCS is used to guide drug product development and determine if in vivo bioequivalence studies can be waived based on in vitro dissolution testing.
This document discusses bioequivalence studies. It begins with an introduction and objectives. It then defines bioequivalence according to the FDA and WHO as the rates and extents of active ingredients being available between two products. It discusses the need for bioequivalence studies for generic approval and reasons for in vivo studies. It also covers study designs, types of evidence to establish bioequivalence, statistical evaluation of data, and biowaivers. The overall purpose is to ensure generic drugs are equivalent to their brand name counterparts in performance.
Properties of GI tract, pH partition hypothesis Naveen Reddy
Drug absorption from the gastrointestinal (GI) tract depends on several physiological factors:
1) Gastric emptying and intestinal transit time influence drug absorption by determining how long drugs remain in areas where absorption can occur. Faster emptying and transit generally increase absorption rate.
2) Water fluxes in the GI tract can impact drug dissolution and movement within the lumen, affecting absorption. Considerable water is secreted in the small intestine and mostly reabsorbed.
3) The permeability of drugs is affected by their solubility, ionization state, and lipophilicity, which determine how well drugs can pass through membranes according to the pH partition hypothesis. However, the microclimate pH at the membrane surface can differ
Rate limiting steps in drug absorption [autosaved]Nagaraju Ravouru
Rate limiting steps in drug absorption 1.Disintegration time
2.Dissolution and solubility
3.Physical and chemical nature of active drug substance
4.Nature of excipients
5.Method of granulation
6.Dissolution test conditions
7.Gastric emptying
study design for bioavailability and bioequivalencePriya Rajput
Bioavailability is the fraction of an administered dose of a drug that reaches systemic circulation. It is 100% for intravenous administration but generally decreases for other routes due to incomplete absorption and first-pass metabolism. There are two types of bioavailability - absolute and relative. Bioequivalence assesses the expected in vivo biological equivalence of two drug preparations and is determined when there is no more than 20% difference in AUC and Cmax between formulations. In vivo bioequivalence studies involve pharmacokinetic and pharmacodynamic methods to measure these parameters from plasma and urine data.
The document discusses comparison of dissolution profiles through different methods and establishing an IVIVC (in vitro-in vivo correlation). It provides definitions of dissolution profile and objectives of comparing profiles. Various methods for comparing profiles are described, including graphical, statistical, and model-dependent/independent methods. Key factors for determining similarity between dissolution profiles using statistical methods like difference factor and similarity factor are outlined. The importance of developing an IVIVC to reduce costs and the need for bioavailability studies is also mentioned. A research article comparing different brands of metformin tablets using tests like dissolution rate, drug content and disintegration is briefly summarized.
The document discusses the Biopharmaceutics Classification System (BCS), which is a framework developed by the FDA to classify drugs based on their aqueous solubility and intestinal permeability. The BCS aims to improve drug development and review processes by identifying when clinical bioequivalence tests are not necessary. It classifies drugs as Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability) or Class IV (low solubility, low permeability) based on their solubility and permeability parameters. The classification can help determine if in vitro dissolution tests alone can demonstrate bioequivalence or if in vivo testing is still required.
The three main rate limiting steps in drug absorption from oral solid dosage forms are disintegration, dissolution, and gastric emptying. Disintegration involves the breakdown of the solid dosage form into smaller particles so that the drug can be released. Dissolution is the process by which the drug becomes dissolved in water to be absorbed. Gastric emptying determines how quickly the drug formulation moves from the stomach into the intestines, where most absorption occurs. Several drug and formulation properties can impact these steps and influence overall drug absorption.
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 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.
Methods For Assesment Of Bioavailability Anindya Jana
This document summarizes a seminar presentation on methods for determining bioavailability. It defines bioavailability as the rate and extent to which the active substance of a drug is absorbed and available at the site of action. It then describes the main objectives of bioavailability studies which include aiding new drug and formulation development. The key methods discussed for assessing bioavailability include measuring plasma drug concentration, urinary drug excretion, acute pharmacodynamic effects, clinical observations, and in vitro drug dissolution studies. Specific parameters are defined for each method such as Cmax, AUC, tmax, Du, and Emax. Finally, the document summarizes two literature articles that developed formulations to enhance the oral bioavailability of curcumin and edarav
it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.
The document discusses the pH partition hypothesis, which states that the absorption of drugs across biomembranes is governed by the drug's dissociation constant (pKa), lipid solubility of the un-ionized form, and the pH of the absorption site. According to the hypothesis, only the un-ionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its un-ionized form can be calculated using the Henderson-Hasselbach equation based on the drug's pKa and the pH. However, the pH partition theory is an oversimplification and does not always accurately predict drug absorption behavior.
This document discusses drug product performance and bioequivalence studies. It defines drug product performance as the release of the drug substance from the product leading to bioavailability, which relates to clinical safety and efficacy. Bioequivalence studies compare formulations and are used to assess the impact of changes to the drug substance, formulation, or manufacturing process. They can be conducted in vivo using pharmacokinetic or pharmacodynamic endpoints or in vitro using dissolution studies.
permeation enhancers by Hemant Chalaune ist M pharm Gaule Jeevan
This document discusses skin as a drug delivery route and permeation enhancers. It begins with an overview of skin structure and properties that create a barrier to drug delivery. It then discusses permeation enhancers, classifying them as chemical or physical and describing examples from each class. The document explains several specific permeation enhancers in depth, including their proposed mechanisms of action, such as disrupting lipid packing or increasing hydration. It concludes that permeation enhancers are crucial components for improving drug bioavailability through the skin.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
This document discusses methods for comparing drug dissolution profiles, which provide information about how completely and quickly an active pharmaceutical ingredient is released from its dosage form. Graphical and statistical methods are described for directly comparing dissolution curves. Model-dependent approaches apply kinetic models like zero-order, first-order, and Higuchi models to the data. Model-independent methods calculate similarity factors f1 and f2 that provide single values for comparing profiles. Comparing dissolution profiles is important for evaluating drug release and bioequivalence of pharmaceutical formulations.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
The document provides an overview of drug dissolution including:
- Definitions of dissolution rate and intrinsic dissolution rate.
- Theories of drug dissolution including the diffusion layer model, Danckwert's model, and the interfacial barrier model.
- Factors that affect drug dissolution related to the physicochemical properties of drugs, drug product formulation, processing factors, dissolution apparatus and test parameters.
- Importance and applications of drug dissolution testing in product development, quality assurance, stability assessment, and biowaivers.
The document discusses various dissolution models that describe drug release from pharmaceutical dosage forms. It begins by defining dissolution and explaining the need for dissolution models. It then describes several common dissolution models - the diffusion layer model, Dankwaet's model, interfacial barrier model, Higuchi model, Korsemeyer-Peppas model, and Baker-Lonsdale model. Each model makes different assumptions about the drug release mechanisms and can be used to analyze dissolution data using mathematical equations. In conclusion, dissolution models provide a quantitative way to interpret dissolution results and describe drug release profiles.
In-vitro in vivo dissolution correlation BCS classificationRoshan Bodhe
The document discusses in vitro in vivo correlation (IVIVC) and the Biopharmaceutical Classification System (BCS). It introduces the BCS, which classifies drugs based on their solubility and permeability. Drugs fall into four classes based on these properties, with Class I drugs being highly soluble and permeable. The document discusses factors that determine drug absorption like solubility, permeability, and dissolution. It describes methods to determine these properties and outlines the common dissolution apparatus and factors affecting dissolution testing. The goals of BCS and examples of drugs in each class are also provided.
The document provides an overview of the Biopharmaceutics Classification System (BCS). The BCS classifies drugs into four classes based on their aqueous solubility and permeability characteristics. Class I drugs are highly soluble and permeable. Class II drugs are highly permeable but poorly soluble. Class III drugs are highly soluble but poorly permeable. Class IV drugs exhibit low solubility and permeability. The BCS is used to guide drug product development and determine if in vivo bioequivalence studies can be waived based on in vitro dissolution testing.
biopharmaceuticals classification system and biowaiverRavish Yadav
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
The document summarizes the biopharmaceutical classification system (BCS), which classifies drugs into four classes based on their aqueous solubility and permeability characteristics. The BCS takes into account solubility, permeability and dissolution rate to predict a drug's absorption and bioavailability. Class I drugs are highly soluble and permeable; Class II are poorly soluble but highly permeable; Class III are highly soluble but poorly permeable; Class IV are both poorly soluble and permeable. The choice of dissolution medium depends on the drug class and aims to simulate gastrointestinal conditions. Understanding a drug's BCS class helps predict its in vivo performance and determine if in vitro dissolution testing can substitute for in vivo bioequivalence studies.
The key factors affecting drug absorption from oral formulations are drug solubility and dissolution rate. The two critical rate-determining steps are the rate of drug dissolution and the rate of permeation through the gastrointestinal membrane. Drug solubility and permeability classify drugs into four Biopharmaceutics Classification System classes. In vitro drug dissolution tests aim to maintain sink conditions to obtain a good correlation with in vivo absorption, such as by increasing fluid volume, partitioning dissolved drug, or adding solvents or adsorbents. Dissolution models account for changing surface area as particles dissolve over time.
The key factors affecting drug absorption from oral formulations are drug solubility and dissolution rate. The two critical rate-determining steps are the rate of drug dissolution and the rate of permeation through the gastrointestinal membrane. Drug solubility and permeability classify drugs into four Biopharmaceutics Classification System classes. In vitro drug dissolution tests aim to maintain sink conditions to obtain a good correlation with in vivo absorption, such as by increasing fluid volume, partitioning dissolved drug, or adding solvents or adsorbents. Dissolution models account for changing surface area as particles dissolve over time.
Pharmacy presentation about BCS classification its criteria.Biowaiever and its conditions .permeability studies in vivo,invitro,in situ.mpharmacy b pharmacy pharmaceutics
The document discusses the Biopharmaceutical Classification System (BCS), which classifies drug substances based on their aqueous solubility and intestinal permeability. The BCS categorizes drugs into four classes and can be used to guide formulation strategies. It provides a framework for biowaivers where in vivo bioequivalence studies are not required for highly soluble, highly permeable Class I drugs and highly soluble Class III drugs, if the drug products dissolve rapidly. The BCS aims to improve drug development efficiency by identifying bioequivalence tests that can be waived.
The document discusses the Biopharmaceutics Classification System (BCS) and biowaivers. It begins by explaining per oral drug administration and factors affecting oral drug absorption like solubility, permeability, and dissolution. It then covers the Lipinski rule of five, BCS classification parameters, and four drug classes. Class boundaries and criteria for biowaivers are outlined. Biowaivers can save time and money by waiving bioequivalence studies for drugs that meet BCS criteria of being highly soluble and permeable. The significance of biowaivers in drug development is also highlighted.
A review on waiving in vivo bioequivalence tests or Biovaiwer, with a case review on the biowaiver monograph on Ibuprofen by H. POTTHAST, J.B. DRESSMAN, H.E. JUNGINGER, K.K. MIDHA, H. OESER, V.P. SHAH,
H. VOGELPOEL, D.M. BARENDS
in J Pharm Sci 94:2121–2131, 2005
Explaining different approaches to waive different BCS class medicines based on their solubility and permeability, as is described by FDA and WHO
Biopharmaceutics classification system class 1Aloysiatreslyn
Biopharmaceutics classification system class
defination,bcs,class1 drugs,physiochemical parameters,advantages,disadvantages,list of drugs,formulaton consideration,solubility,permability,disssolution etc .The Biopharmaceutics Classification System is a system to differentiate the drugs on the basis of their solubility and permeability. This system restricts the prediction using the parameters solubility and intestinal permeability.
Bioavailability and bioequivalence studyMcpl Moshi
BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
Kashikar V S
PES Modern College of Pharmacy ( for ladies), Moshi Pune
Bioavailability and Bioequivalence studyMcpl Moshi
Bioavailability and Bioequivalence study, BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.
It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.
BCS Guideline for solubility and Dissolution.pptxImdad H. Mukeri
Briefly explanation of The Biopharmaceutics Classification System (BCS) of drug substance
and its solubility in the pH range of 1–7.5, absorption or intestinal membrane permeability
This document discusses key topics related to pharmacology including bioavailability, bioequivalence, and therapeutic index. It provides background on how bioavailability was studied initially due to toxicity issues with certain drugs. Factors that influence bioavailability include pharmaceutical factors like formulation, patient factors like metabolism, and route of administration. Bioequivalence compares the bioavailability of two drugs to determine if they are therapeutically equivalent. The therapeutic index is the ratio of toxic to therapeutic doses - a higher index is preferable as it means toxicity occurs at a much higher dose level.
This document provides an overview of pharmacokinetics and drug absorption. It defines key terms like bioavailability, discusses factors that influence drug absorption like lipid solubility and ionization, and mechanisms of drug transport including passive diffusion. Specific topics covered include the first-pass effect, importance of drug and environmental pH on absorption, and how molecular weight impacts absorption. Measurement of areas under the curve is presented as a method for assessing bioavailability.
This presentation discusses biowaivers, which allow waiver of in vivo bioavailability and bioequivalence studies. It covers:
- What a biowaiver means and the need for developing alternatives to in vivo studies.
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Dissolution and In Vitro In Vivo Correlation (IVIVC)
1. IN VITRO IN VIVO
CORRELATION
(IVIVC)
Presented By: Harneet Kaur, Jaspreet Singh
2. Contents
Introduction to BCS
Classification
Determination of Solubility, Permeability & Dissolution
Comparison of Dissolution Profile
Limitations of BCS
Extensions To BCS
IVIVC and its Levels
Predictability
IVIVR, IVIVM and IVIVP
IVIVC for parenterals
Applications of IVIVC
Softwares used for IVIVC
3. Introduction to BCS
The Biopharmaceutical Classification System (BCS) is a
framework for classifying drug substances based on their
aqueous solubility and intestinal permeability.
G. L. Amidon, Vinod P. Shah, Hans Lennernas, and John R. Crison
gave this concept in 1994.
The classification system is based on Fick’s first law applied to a
membrane:
Jw= Pw Cw
Where,
Jw = Drug flux (mass/area/time) through the intestinal wall
at any position and time.
Pw = Permeability of membrane
Cw = Drug conc. at membrane
4. Introduction to BCS
Whenever a dosage form is administerd orally, the events that
follow are:
Solid
dosage
form
Disintegration Solid
dosage
particles
Dissolution Drug in
solution at
absorption
site
Systemic
Circulation
Permeation
across the
GIT Barrier
5. Drug absorbance from a solid dosage form following oral
administration depends on:
Release of drug substance from drug
product
Dissolution of drug under physiological
conditions
Permeability across the GI tract
Introduction to BCS
6. Boundaries Used in BCS
Highly soluble
A drug substance is considered highly soluble when the highest
dose strength is soluble in 250mL water over a pH range 1 to 7.5.
Highly permeable
A drug substance is considered highly permeable when the
extent of absorption in humans is determined to be 90%of an
administered dose, based on the mass balance or in comparison
to intravenous dose.
Rapidly dissolving
A drug product is considered to dissolve rapidly when 85% of
the labeled amount of drug substance dissolves within 30
minutes, using USP apparatus I or II in a volume of 900mL buffer
solution.
7.
8. Contd…
The BCS additionally proposes 3 dimensionless ratios
to classify drug absorption:
Absorption Number
Dissolution Number
Dose Number
9. Absorption Number (An)
Defined as the ratio of the mean residence time of the drug in GIT
to the mean absorption time.
An = MRT/MAT
Ideally An>1
It’s the corresponding dimensionless parameter for permeability.
Lower permeability decreases the ratio.
where,
Peff is the effective permeability,
tres is mean residence time and;
R is the radius of intestinal segment.
Contd…
10. Dissolution Number (Dn)
Defined as the ratio of mean residence time to mean dissolution
time
Ideally, Dn >1
Inadequate solubility, diffusivity, excessive particle size reduce
this ratio
It’s the corresponding dimensionless parameter for dissolution
rate
Contd…
11. Dose Number (D0)
Defined as the mass of the drug divided by an of uptake volume
(250 mL) and solubility of drug.
Ideally D0 <1 for full dissolution in principle .
It’s the corresponding dimensionless parameter for solubility.
where,
M0 is dose,
Cs is saturation solubility and;
V0 is initial gastric volume (≈250ml).
Contd…
12. Goals of BCS
To identify the challenges of formulation Design.
To guide decisions w.r.t IVIVC.
To improve the efficiency of drug development and identifying
expendable clinical bioequivalence tests.
To explain when a waiver for in vivo bioavailability and
bioequivalence may be requested.
To assist in QC in SUPAC.
To recommend a class of immediate-release (IR) solid oral
dosage forms for which bioequivalence may be assessed based on
in vitro dissolution tests.
13. Class I drugs
The drugs of this class exhibit high absorption number and high
dissolution number.
For those class 1 drugs formulated as IR products, dissolution rate
generally exceeds gastric emptying.
Behave like an oral solution in-vivo.
The rate-limiting step is gastric emptying.
These compounds are well absorbed.
Absorption rate is usually higher than the excretion rate.
14. Class II drugs
The drugs of this class have a high absorption number but a low
dissolution number.
In vivo drug dissolution is then a rate-limiting step for absorption
except at a very high dose number.
The absorption for Class II drugs is usually slower than for Class I
and occurs over a longer period of time.
The bioavailability of these products is limited by their solvation
rates.
Hence, a correlation between the in vivo bioavailability and the in
vitro solvation can be found.
15. Class III drugs
Drug permeability is the rate-limiting step for drug absorption,
but the drug is solvated very quickly.
These drugs exhibit a high variation in the rate and extent of drug
absorption.
Since the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather than
the dosage form factors.
16. Class IV drugs
The drugs of this class are problematic for effective oral
administration.
These compounds have poor bioavailability.
They are usually not well absorbed through the intestinal mucosa,
and a high variability is expected.
Fortunately, extreme examples of Class IV compounds are the
exception rather than the rule, and these are rarely developed
and marketed. Nevertheless, several Class IV drugs do exist.
19. Sub Classes of BCS Class II
Drugs
Basis- significant impact of pka on the solubility and dissolution
of drugs.
BCS Class II drug product dissolution in vitro as well as in vivo is
highly dependent on acidic or basic nature of drug.
Hence, the class II drugs are subclassified as:
Class IIa drugs
• Weakly
Acidic Drugs
• pka ≤ 5
Class IIb Drugs
• Weakly Basic
Drugs
• pka ≥ 6
Class IIc Drugs
• Neutral
Drugs
20. Sub Classes of BCS Class II
Drugs
Various pH conditions in the gastro-intestinal tract:
21. Sub Classes of BCS Class II
Drugs
Class IIa Drugs
Drugs are insoluble at gastric pH & soluble at intestinal pH
At intestinal pH (~6.5), the dissolution would increase upto
100 times
Hence, dissolution rate would be faster than gastric
emptying rate
Thus, these drugs reflect gastric emptying and luminal pH
differences.
Examples- ibuprofen and ketoprofen
22. Sub Classes of BCS Class II
Drugs
Class IIb Drugs
Exhibit high solubility and dissolution rates at acidic pH in
stomach
May precipitate in intestinal pH
Examples- carvedilol and ketoconazole
Class IIc Drugs
Solubility is not affected by in vivo pH change
Example- fenofibrate and danazole
25. Sub Classes of BCS Class II
Drugs
Results:
Ibuprofen and ketoprofen are absorbed more in the distal
small intestine than in the proximal small intestine due to
the environmental pH in the GI tract and their pH-
dependent solubility/dissolution.
Major absorption of ketoconazole and carvedilol is at lower
pH environment in duodenum and proximal jejunum due to
higher solubility at this region of intestine.
Fenofibrate and danazole show constant dissolution profile
throughout the dissolution profile, hence show slow and
prolonged absorption.
26. Determination of Solubility
Solubility is the amount of a substance that has passed into
solution when equilibrium is attained between the solution and
excess (i.e., undissolved) substance at a given temperature and
pressure.
Determined by exposing an excess of solid (drug) to the liquid in
question (water/buffer) and assaying after equilibrium.
Temperature: 37±1 °C
pH: 1-7.5 (as per FDA Guidelines)
1.2- 6.8 (as per WHO Guidelines)
Media: Standard buffer solutions as per USP
Most used method: Shake Flask Method
27. Determination of Permeability
Effective permeability (P) is generally described in terms of units
of molecular movement distance per unit time (e.g. 10 cm/ s).
High permeability drugs- with an extent of absorption greater
than or equal to 90% and are not associated with any
documented instability in the gastrointestinal tract.
The permeability is based directly on the extent of intestinal
absorption of a drug substance in humans or indirectly on the
measurements of the rate of mass transfer across the human
intestinal membrane.
The methods range from simple oil/water (O/W) partition
coefficient to absolute bioavailability studies.
28. Determination of Permeability
Human Studies
Mass balance pharmacokinetic studies
Absolute bioavailability studies, intestinal perfusion
Methods
Intestinal Permeability Methods
In vivo intestinal perfusions studies in humans
In vivo or in situ intestinal perfusion studies in animals
In vitro permeation experiments with excised human or
animal intestinal tissue
In Vitro Permeation Experiments
Across epithelial cell monolayers (e.g., Caco-2 cells or
TC-7 cells)
29. Determination of Dissolution
A powerful and a useful method for determining:
The product quality
Clinical performance of dosage form
Batch to batch consistency
Bioequivalence/ bioinequivalence
Provides an insight to in vivo behavior
Dissolution performance is influenced by:
Physicochemical properties of the substance
Physiological conditions in the GIT tract
However these can vary between fasted- and fed-states as
well as within and among subjects.
31. Dissolution Apparatus
Type USP BP
Apparatus 1 rotating basket Rotating basket
Apparatus 2 paddle paddle
Apparatus 3 reciprocating cylinder flow-through cell
Apparatus 4 flow-through cell
Apparatus 5 paddle over disk
Apparatus 6 cylinder
Apparatus 7 reciprocating disk
32. USP 30 classification
1. Rotating Basket (Ph.Eur./BP/JP)
2. Paddle (Ph.Eur./BP/JP)
3. Reciprocating Cylinder (Ph.Eur.)
4. Flow Through Cell (Ph.Eur./BP/JP)
5. Paddle Over Disk (Ph.Eur.)
6. Rotating Cylinder (Ph.Eur.)
7. Reciprocating Holder
Official Dissolution Apparatus
33. Useful for
• capsules
• beads
• delayed release / enteric
coated dosage forms
• floating dosage forms
• surfactants in media
Standard volume
• 900/1000 mL
• 1, 2, 4 L vessels
Apparatus 1 - Basket
34. disintegration-dissolution
interaction
hydrodynamic „dead zone“
under the basket
degassing is particularly
important
limited volume
sink conditions for poorly
soluble drugs
Advantages Disadvantages
breadth of experience (>
200 monographs)
full pH change during the
test
can be easily automated
which is important for
routine work
Apparatus 1 - Basket
36. Useful for
• tablets
• capsules
• beads
• delayed release / enteric
coated dosage forms
Standard volume
• 900/1000 ml
Method of first choice !!!
Apparatus 2 - Paddle
37. easy to use
robust
can be easily adapted
to apparatus 5
long experience
can be easily automated
which is important for
routine investigations
pH/media change is difficult
limited volume sink
conditions for poorly soluble
drugs
hydrodynamics are complex
coning
sinkers for floating dosage
forms
Advantages Disadvantages
Apparatus 2 - Paddle
38. Sinkers Coning
A small loose piece of nonreactive material such as
not more than a few turns of wire helix may be
attached to dosage units that would otherwise
float.
Apparatus 2 - Paddle
40. Useful for
• tablets
• beads
• controlled release formulations
Standard Volume
• 200-250 mL per station
Apparatus 3 – Reciprocating
Cylinder
41. Advantages
• easy to change the pH
• hydrodynamics can be
directly influenced by
varying the dip rate
Disadvantages
• small volume (max. 250 mL)
• little experience
• limited data
Apparatus 3 – Reciprocating
Cylinder
42. Useful for
• low solubility drugs
• microparticulates
• implants
• suppositories
• controlled release formulations
Variations
• open system
• closed system
Apparatus 4 – Flow-Through
Cell
44. Advantages
• easy to change media pH
• pH-profile possible
• sink conditions
• different modes
a) open system
b) closed system
Disadvantages
• Deaeration necessary
• high volumes of media
• labor intensive
Apparatus 4 – Flow-Through
Cell
45. Useful for
• transdermal patches
Standard Volume
• 900 mL
Advantages
• standard equipment
(paddle) can be used, only add
a stainless steel disk assembly
Disadvantages
• disk assembly restricts
patch size
Apparatus 5 – Paddle Over
Disk
46. Useful for
• transdermal patches
Similar to apparatus 1
Instead of basket, a stainless steel
cylinder holds the sample
Apparatus 6 – Rotating
Cylinder
47. Useful for
• Transdermal products
• Non-disintegrating controlled
release preparations
Samples are placed on holders using
inert porous cellulosic support.
It reciprocates vertically at
frequency of 30 cycles/sec.
The test is carried out at 32°C.
Apparatus 7 – Reciprocating
Holder
48. Dissolution Media
Aqueous media is the most preferred.
0.1N HCl – to simulate gastric media
Simulated Intestinal Fluid (SIF)
Phosphate buffers of various pH
Fasted State Simulated Intestinal Fluid (FaSSIF)
Fed State Simulated Intestinal Fluid (FeSSIF)
TRIS Buffered Saline (TBS)
49. Selection of Dissolution
Media
• Simulated gastric fluid
(without enzymes)
• Simulated intestinal fluid
(without enzymes)
Class I
&
Class III
• SGF plus surfactant
• Milk with 3.5%fat
• SIF
Class II
&
Class IV
50. Comparison of Dissolution
Profile
A model-independent mathematical approach is used
to compare the dissolution profile of two products:
To compare the dissolution profile between T (generic,
multisource) product & R (comparator) product in
biowaiver conditions
To compare the dissolution profile between the two
strengths of products from a given manufacturer
For SUPAC after the product is approved
51. To compare the dissolution profile, two factors are
determined:
Difference
factor (f1) Similarity
factor (f2)
Comparison of Dissolution
Profile
52. Difference Factor
The difference factor calculates the percent difference
between the two curves at each time point and is a
measurement of the relative error between the two curves.
Where:
Rt: reference assay at time point t
Tt: test assay at time point t
n: is the number of dissolution time points
53. f1 Equation:
approximates the error between two curves
% Error is zero when the test & reference profiles are
identical
% Error increases as the dissimilarity between 2
profiles increases
Difference Factor
54. Similarity Factor
The similarity factor is a logarithmic reciprocal square root
transformation of the sum squared error and is a
measurement of the similarity in the percent dissolution
between the two curves.
Where:
Rt: reference assay at time point t
Tt: test assay at time point t
n : is the number of dissolution time points
55. f2 Equation:
takes the average sums of square of the difference
between the test & reference profiles
the results fit between 0 & 100
fit factor is 100 when the profiles are identical
fit factor approaches zero as the dissimilarity increases
Similarity Factor
56. Limitations of BCS
Effects of Food, Absorptive transporters, Efflux transporters
& Routes of elimination (renal/biliary) are important
determinants of BA for immediate release oral dosage
forms, which are not considered in BCS.
BCS based biowaivers are not applicable for the following:
Narrow therapeutic range drug products.
Limited application for the class II drugs and not
applicable for class III.
Dosage form meant for absorption in the oral cavity e.g.
sublingual or buccal tablets.
57. Extensions to BCS
1. Six class BCS:
The drugs are classified into six classes.
The solubility was classified as “low” or “high” and the
permeability was allotted as “low” “intermediate” or “high”.
2. Quantitative BCS (QBCS):
Quantitative BCS (QBCS) was developed using the
dose: solubility ratio as core parameter for classification.
States that solubility is a static equilibrium parameter and
cannot describe the dynamic character of the dissolution
process for the entire dose administered.
58. Extensions to BCS
3. Pulmonary BCS
The BCS is limited to the gastrointestinal tract.
The pulmonary BCS (PBCS) consider the specific biology of the lung
as well as particle deposition, aerosol physics, and the subsequent
processes of drug absorption and solubility
4. BDDCS CLASSIFICATION
BDDCS (Biopharmaceutical Drug Disposition and Classification
System) divides compounds into four classes based on their
permeability and solubility.
This classification system is useful in predicting effects of efflux and
uptake transporters on oral absorption as well as on post
absorption systemic levels following oral and intravenous dosing.
59.
60. Difference Between BCS &
BDDCS
BCS BDDCS
It takes into account solubility and
permeability criteria to classify drugs.
It takes into account solubility and
metabolism criteria.
It is more ambiguous. It is less ambiguous.
Less number of drugs are available
for biowaiver.
More number of drugs are available
for biowaiver.
It is not applicable in condition where
food and transporter interaction
occur.
It is applicable in condition where
food and transporter interaction
occur.
62. Systemic absorption of drugs is a prerequisite for eliciting
their therapeutic activity, whenever given non-
instantaneously.
As per federal guidelines, all the oral dosage forms have to
be evaluated for their in vivo bioavailability.
Thus, generic manufacturers must provide detailed
bioequivalence evidence showing head-to-head comparative
performance of their product against reference.
Conduct of such biostudies is a Herculean task involving
myriad technical, economical and ethical issues.
Also, development and optimization of a formulation is an
time consuming and costly process.
Concept of IVIVC
63. This may require alteration in formulation composition
manufacturing process, equipment and batch size.
These type of changes call for the need of BA studies to prove
that new formulation is bioequivalent with the old one.
Implementation of these requirements :
halt the marketing of new formulation
increase the cost of optimization process
demand for strict regulatory guidelines to be followed
Thus, it would be very convenient if inexpensive in vitro
experiments could be substituted for in vivo bioavailability
tests.
Concept of IVIVC
64. For in vitro test to be useful in this context, it must predict in
vivo behavior to such an extent that in vivo bioavailability test
becomes redundant.
In vitro dissolution is one such test that can predict the in vivo
performance of a drug.
For in vitro dissolution to act as surrogate for bioavailability
studies an accurately validated correlation needs to be
established between in vitro and in vivo performance of drug.
Thus, by establishing IVIVC , in vitro dissolution can act as
surrogate for bioequivalence studies.
This would circumnavigate the hiccups caused by the
biostudies by seeking for requisite biowaivers.
Concept of IVIVC
65. The concept of IVIVC has been extensively discussed for
modified release dosage forms.
This is because the dissolution behavior of of the drug from ER
or MR product is the rate limiting factor for absorption in GIT.
This is why IVIVC are expected more generally for ER
formulations than with IR products especially when the latter
releases the drug rapidly (>80 % in < 20 minutes)
But, it does not mean that IVIVC cannot be applied for IR
products.
In recent times, IVIVC for parenterals, transdermals,
pulmonary formulations etc. are also coming.
Concept of IVIVC
66. What is Correlation?
The word Correlation has two different definitions:
Mathematical
Biopharmaceutical
Mathematically- the word correlation means
interdependence between qualitative and quantitative
data, or relationship between measurable variable or rank.
From Biopharmaceutical point of view, it simply means
relationship between observed parameters derived from in
vitro and in vivo studies.
67. IVIVC - Definition
• A predictive mathematical model describing the relationship
between an in vitro property of dosage form (usually the
rate or extent of drug dissolution or release) and a relevant
in vivo response, e.g., plasma drug concentration or amount
of drug .
FDA
• The establishment of a relationship between a biological
property or a parameter derived from a biological
property (Cmax, AUC) produced by a dosage form, and a
physicochemical characteristic (in vitro release) of the
same dosage form.
USP
68. The purpose of in vitro dissolution studies in the early stages
of drug development is to:
Select the optimum formulation
Evaluate the active ingredient and excipients.
Assess any minor changes in the drug products
From IVIVC point of view in vitro dissolution is proposed to be
a surrogate of drug bioavailability studies.
This is possible only if an accurately validated IVIVC is
established.
Dissolution as Surrogate for
BA Studies
69. If a valid correlation of in vitro dissolution is established with
in vivo performance of the formulation then it can be used
to:
Assess batch to batch consistency
Distinguish acceptable and unacceptable i.e. bioequivalent and
bioinequivalent drug products
Ensure product quality i.e. ability to manufacture the product
reproducibly and maintain its release properties throughout
shelf-life
Provide insight to in vivo behavior of product
Guide development of new formulations
Dissolution as Surrogate for
BA Studies
70. Establishment of Dissolution
Standards
Dissolution test results depend upon various dissolution test
conditions such as pH, volume, ionic strength, deaeration,
dissolution medium, surfactants, agitation and temperature.
Dissolution results may vary with change in dissolution
conditions.
So, establishment of proper dissolution standards reflecting in
vivo performance of a drug is important.
No single dissolution test conditions can be applied to all drugs.
71. Need of IVIVC
Setting up of an in vitro release test that would serve as a
surrogate for in vivo plasma profiles ( bioequivalence testing).
To minimize unnecessary human testing;
To set up biopharmaceutically meaningful in vitro release
specifications.
Decreased regulatory burdens.
Minimization of cost and time required in additional
bioavailability studies
72. History
1987
• FDA-sponsored workshop entitled Report on CR Dosage Forms:
Issues and Controversies (1987) - did not permit consistently
meaningful IVIVC for ER dosage forms
1988
• A USP PF Stimuli article established different IVIVC Levels
1990
• FDA-sponsored workshop entitled In vitro/In vivo Testing and
Correlation for Oral Controlled/Modified Release Dosage Forms
(1990) concluded that the development of an IVIVC was an
important objective on a product-by-product basis.
1993
• FDA-sponsored workshop entitled Scale-up of Oral Extended
Release Dosage Forms (1993) identified dissolution as a surrogate
for bioequivalency testing.
73. 1995
• Amidon and Lennernäs et al. proposed BCS to utilise in vitro
dissolution tests as a surrogate for in vivo bioequivalence studies .
1997
• FDA published regulatory guidances for in vitro-in vivo correlations
(IVIVC)
• EMEA followed suit in 2000.
2000
• FDA introduced regulatory guidlines for BCS biowaivers .
• EMEA guidelines came in 2002.
2005
• IVIVC and IVIVR established tools
History
74. LEVELS OF CORRELATION
Based on the ability
of the correlation to
reflect the complete
plasma level profile,
which will result from
administration of the
given dosage form.
LEVEL A
LEVEL B
LEVEL C
MULTIPLE LEVEL C
LEVEL D
74
75. LEVEL A CORRELATION
Highest category of correlation
Linear correlation
Superimposable in vitro and in vivo input curve
Or can be made superimposable by use of a constant offset
value
Represents point to point correlation between in vitro
dissolution time course and in vivo response time course
Utilizes all the dissolution and plasma level data available to
develop correlation
Most informative and useful from a regulatory perspective
76. Deconvolution: it is the process where output (plasma
concentration profile) is converted into input (in vivo
dissolution of dosage form)
The plasma or urinary excretion data obtained in the
definitive bioavailability study of MR dosage form are
treated by deconvolution.
The resulting data represent the in vivo input rate of the
dosage form.
It can also be called in vivo dissolution when the rate
controlling step is dissolution rate.
Any deconvolution procedure will produce the acceptable
results.
Developing Level A
Correlation
77. • WN Method
• Loo- Riegelman Method
Model Dependent
• Numeric Deconvolution
Model Independent
Deconvolution methods
Developing Level A
Correlation
78. WAGNER NELSONL LOO- RIEGELMAN METHOD
Used for a one compartment
model
Less complicated
The cumulative fraction of drug
absorbed at time t is calculated as:
CT is plasma conc. at time T
KE is elimination rate constant
• Used for multi compartment
system
• More complicated
• Fraction absorbed at any time t is
given by:
Xp)T is amount of drug in peripheral
compartment as a function of time
Vc is apparent volume of distribution
K10 is apparent first order elimination
rate constant
Developing Level A
Correlation
79. Numeric Deconvolution Approach
Alternative approach requiring in vivo plasma data from an
oral solution or iv dose
Based on convolution integral equation
The absorption rate rabs that results isn plasma concentration
c(t) may be estimated by solving following eq.
Cδ is the concentration time profile resulting from instantaneous absorption of a
unit amount of drug which is typically absorbed from bolus IV injection or
reference oral solution data
c(t) is plasma conc. versus time profiles of tested formulation
rabs is the input rate of the oral solid dosage form in to the body
u is the variable of integration
Developing Level A
Correlation
80. Y(t) = G(t) X(t)
Where Y(t) is the function describing plasma C-t profile following
extravascular administration,
G(t) is the function describing the Concentration-time profile following
bolus iv dose
X(t) is the function describing input i.e. dissolution from dosage form
Deconvolution method requires no assumptions regarding
number of compartments.
It requires data obtained after both oral and intravenous
administration in the same subject.
It assumes no differences in PK of drug distribution and
elimination from one study to the other.
Drug concentrations must be measured at same times
following both oral and iv administration.
Developing Level A
Correlation
81. Biobatch is then subjected to in vitro dissolution evaluation.
In vitro dissolution curve is then compared to drug input
rate curve i.e. in vivo dissolution curve.
To compare Graph b/w Fraction of drug absorbed (FRA) and
Fraction of Drug Dissolved (FRD)is plotted.
Mathematically scale in vivo profile to match with in vitro
profile
Linear correlations – superimposable curves
If not superimposable then can be made by use of scaling
factor.
Nonlinear correlations, though uncommon, are also possible.
Developing Level A
Correlation
83. Convolution Approach
Input is converted into output.
Single step approach
Here in vitro dissolution profile is converted into plasma
concentration time profile.
It can be done by model independent or model dependent
approaches, physiology based softwares and simulation can
be applied.
Then predicted plasma profile is compared with the real
plasma profile.
Developing Level A
Correlation
85. Scaling of Data
Since, significant difference exists between in vitro and in vivo
dissolution conditions, it is not uncommon to see time scale
difference while comparison.
The introduction of time scale factor is acceptable as long as
the same factor is being used for all formulations
In addition to time scale factor, other approaches like lag
time and cut-off factor can be used.
Lag time is used to account for gastric emptying .
Cut off factor is used to account for lack of colon absorption.
Developing Level A
Correlation
86. 1.Types of Formulations used
2.Number of formulations
Minimum 2 formulations with different release rates
But 3 or more formulations with different release rates (slow medium or
fast) recommended
EXCEPTION– conditions independent dissolution where only one
formulation
Condition dependent
dissolution
• Formulations with
different release rates
Condition independent
dissolution
• Single release
formulation
Developing Level A
Correlation
87. 3. Design
Single study cross over design
4. Dissolution conditions
Should adequately discriminate among different formulations
Once a discriminating condition is established, the conditions
should be same for all the formulations.
During the early stages, dissolution conditions can be altered to
develop point-to-point correlation.
5. Time scaling
Should be same for all the formulations
Developing Level A
Correlation
88. ADVANTAGES
They reflect the whole curve because all dissolution and
plasma level data points are used.
They are excellent quality control procedures.
More informative
Very useful from regulatory point of view.
89. Evaluating Predictability
An IVIVC should be evaluated to demonstrate that predictability of
the in vivo performance of a drug product, from the in vitro
dissolution characteristics of the drug product formulations, is
maintained over a range of in vitro release rates
Evaluation approaches focus on estimation of predictive
performance or prediction error.
100*)(%
observed
predictedobserved
PE
90. Internal predictability
• Evaluates how well model
describes the data used to
define IVIVC
• based on the initial data sets
used to define the IVIVC
• Used for wide therapeutic
range drugs
• Used if formulations with 3
or more release rates were
used
External predictability
• Relates how well the model
predicts when one or more
additional data sets are used
• based on additional data
sets obtained from a
different (new) formulation
• Used for narrow therapeutic
range drugs
• Used if formulations with
only 2 release rates were
used
91. Internal predictability
• Acceptance Criteria
• Average %PE of 10% or
less for Cmax and AUC
• %PE for each formulation
should not exceed 15%
• If these criteria are not
met external predictability
should be performed.
External predictability
• Acceptance Criteria
• Average % PE of 10% or
less for Cmax and AUC
• %PE between 10-20%
demands for additional
data sets.
• %PE greater than 20%
indicates inadequate
predictiability
92. Uses the principles of statistical moment analysis
The mean in vitro dissolution time is compared either to the
mean residence time (MRT) or to the mean in vivo
dissolution time.
Is not a point-to-point correlation
Reason - because a number of different in vivo curves will
produce similar mean residence time values.
Level B correlations are rarely seen in NDAs
LEVEL B CORRELATION
94. One dissolution time point (t50% t90% etc.) is compaired to one
mean pharmacokinetic parameter such as AUC, Tmax , Cmax
A single point estimation and does not reflect the entire shape of
plasma drug concentration curve.
Weakest level of correlation
Can be useful in early stages of formulation development when
pilot formulations are being selected
Biowaiver not possible
LEVEL C CORRELATION
95. •
•
•
A
B
C
20 40 10060 80
% drug dissolved in 45 minutes
AUC(μg.h/ml)
10
30
20
10
40
60
50
10
95
LEVEL C CORRELATION
96. MULTIPLE LEVEL C CORRELATION
Relates one or several pharmacokinetic parameters of interest
(Cmax, AUC etc.) to the amount of drug dissolved at several
time points of the dissolution profile
It should be based on atleast 3 dissolution time points
covering early, middle and late stages of dissolution profile.
If such correlation is achievable; then development of level A is likely and
preferred
May be used to justify biowaiver, provided that the correlation has been
established over the entire dissolution profile with one or more
pharmacokinetic parameters of interest
97. LEVEL D CORRELATION
Level D correlation is a rank order and qualitative analysis and is
not considered useful for regulatory purposes.
It is not a formal correlation but serves as an aid in the
development of a formulation or processing procedure.
98. General Considerations
Number of subjects = 6-36
Cross over studies preferred, but parallel or cross studies also
possible
The reference product may be iv solution, an aqueous oral
solution or an immediate release product.
IVIVCs are developed in fasted state unless the drug is not
tolerated in fasted state.
The preferred dissolution apparatus is USP basket type or
paddle type at compendial rotation speeds.
The same dissolution method should be used for different
formulations.
99. An aqueous medium, either water or a buffered solution
preferably not exceeding pH 6.8 is recommended.
Sufficient data should be submitted to justify pH greater than
6.8
Non aqueous and hydroalcohlic systems are discouraged
unless all attempts with aqueous media are unsuccessful.
For poorly soluble drugs addition of surfactants may be
appropriate.
The dissolution profile of at least 12 individual dosage units
from each lot should be determined.
General Considerations
101. IVIVC expectations for immediate release products based on BCS
Class Solubility Permeability Absorption rate
control
IVIVC expectations for Immediate
release product
I High High Gastric
emptying
IVIVC expected, if dissolution rate
is slower than gastric emptying
rate, otherwise limited or no
correlations
II Low High Dissolution IVIVC expected, if in vitro
dissolution rate is similar to in vivo
dissolution rate, unless dose is
very high.
III High Low Permeability Absorption (permeability) is rate
determining and limited or no
IVIVC with dissolution.
IV Low Low Case by case Limited or no IVIVC is expected.
102. IVIVC for Parenterals
IVIVC has been successfully applied to solid oral dosage forms
IVIVC can be applied to parenteral Modified Release (MR)
dosage forms as well.
To obtain such a correlation following steps are followed:
Obtain in vivo data
Identify in vivo drug release mechanism
Identify factors affecting in vivo release
Design in vitro release method based on in vivo release mechanism
Correlate the in vitro and in vivo data
For MR release dosage forms, it is often necessary to use an
in vitro method of release testing that exceeds the in vivo
rate of drug release.
103. Development of in vitro Release
Tests
Since these dosage forms are typically designed to release
their contents over periods of weeks, months or even years, it
becomes impractical to wait for a real-time test for batch
release of product.
Therefore, accelerated methods are often developed to assist
in batch release of the product.
Accelerated tests, by their nature, (e.g. elevated temperature
or use of solvents)can change not only the rate of drug
release but also the mechanism of release.
Therefore, it is very important to understand the accelerated
release mechanism.
104. When dealing with MR systems, it is the mechanism of
release that should dictate the science of the in vitro test
method.
Following test methods have been successfully employed:
Modified rotating paddle for suspensions
Franz diffusion cell for gels
Flow through cell for implants
Floatable dialysis bag for nanoparticles or microspheres
USP apparatus for with glass beads for microspheres
Release medium, flow rate, agitation characteristics etc. are
important.
Development of in vitro Release
Tests
105. Real-time data for drug release is essential to correlate to in
vivo bioavailability, accelerated testing can also be used.
For tests intended to support an IVIVC, the release profile from
an accelerated test should correlate with the in vivo release
profile.
Where it is not possible to achieve such a correlation with an
accelerated release test, such a test may still be useful for
batch release of the product.
However, the development of an additional real-time test will
still be needed if the intent is to develop an in vitro test that is
predictive of in vivo product performance.
Developing an IVIVC for Parenteral
Products
106. Accelerated testing will often result in a change in the
mechanism of release.
Nevertheless, accelerated conditions can still serve as a
discriminatory tool so long as all formulations experience
similar changes and continue to exhibit performance
characteristics that can be differentiated from each other.
In some cases, a correlation between in vivo data and
accelerated in vitro data may be obtained, regardless of a
change in the mechanism of release.
However, there are numerous other situations where the use
of accelerated test conditions maybe problematic.
Developing an IVIVC for Parenteral
Products
107. For example, some MR dosage forms are associated with
multiphasic release characteristics, such as an initial burst
release followed by a secondary release phase.
It is often impossible to separate these different phases in an
accelerated test.
For that reason, “real-time” test is often needed to
characterize the initial burst phase.
The initial burst release phase is usually diffusion controlled,
whereas the later phases tend to be controlled by erosion and
diffusion.
Developing an IVIVC for Parenteral
Products
109. In this scheme, there are three output functions which are
used to establish IVIVC,
X1 in vitro release profile correlated to either Y1 (defined as disappearance
profile from the administration site,
X1 related to or plasma concentration time profile as Y2,
X1 to the pharmacological effects of drugs at the target tissue Y3.
If Y2 is used, convolution procedure or any other modeling
technique can be used to relate plasma concentration time
profile to in vivo absorption or release rate.
If a linear relationship between the in vitro and release data
does not occur then, IVIVC can be achieved by mathematical
modeling (e.g.time variant nonlinear modeling) of the in vitro
and in vivo data
Developing an IVIVC for Parenteral
Products
110. In vitro- in silico- in vivo
Correlation
This approach is used in drug discovery and early preclinical
phases where PK data is not available.
IVIVC at this time is usually conducted through in silico
simulation of structural properties of a molecule or high
throughput experimental data generated.
Although simulation is not a replacement for definitive
scientific experiments, it provides in sight what one would
expect in vivo based on physicochemical properties.
There are two in silico approaches for prediction of in vivo
oral absorption:
Statistical models
Mechanism-based models
111. One mechanism based model that has gained popularity in
recent times is GastroPlusTM .
Inputs to software include:
Oral dose
Physiochemical properties (pH-solubility profile, permeability etc.)
Physiological properties (species, GI transit, GI pH, food status etc.)
Formulation properties (release profile, particle size etc.)
PK parameters (optional)
The output includes:
Fraction of oral dose absorbed
Plasma Concentration time profiles (if PK parameters are given)
In vitro- in silico- in vivo
Correlation
112. CASE STUDY
In one relatively simple application of GastroPlus TM, it was
asked whether or not the mean particle size requirement of
Compound I (aqueous solubility>100 mg/mL) may be relaxed
from 35 µm to approximately 100 µm without affecting its
oral bioavailability.
A simulation suggested that the extent of absorption is not
sensitive to changes in particle size in the range of 35–250
µm.
This helps in decision making with respect to dosage form
design.
In vitro- in silico- in vivo
Correlation
113. Failure of Level A IVIVC for IR
Products
For Level A analysis, Fa is plotted against Fd and requires linear
regression of Fa vs Fd.
IVIVC for IR products is less successful as they do not show
dissolution limited absorption.
A reason for this lack of success and acceptance may be the
general failure of the Level A method to immediate release
products.
Controlled release products, rather than immediate release
products, are the focuses in the IVIVC literature.
But it does not indicate that dissolution from such products
fails as a surrogate for bioavailability.
114. Slippery Slope of Correlation
Since dissolution is perhaps not rate-limiting in an IR product,
the Fa against Fd profile will be non-linear.
In practice, a correlation is often taken to imply a linear
relationship which is problematic for IR products.
Thus, avoidance of term “correlation” and use of more
general term that would allow for non-linear relationships
may aid in development of IVIVC-type analysis of IR products.
115. IVIVR
One possible substitution for IVIVC is IVIVR, with "R" denoting
"relationship
IVIVR need not be limited to straight-line relationships, which
appear to be generally incorrect for IR products.
dd
a
a FF
f
F 1
1
1
1
1
1
1
Where,
Fa =fraction of the total amount of drug absorbed at time t,
fa =fraction of the dose absorbed at t = #,
a =ratio of the apparent first-order permeation rate constant (kpaap) to the
first-order dissolution rate constant (kd), and
Fd =fraction of drug dose dissolved at time t.
116. Level A method is a special (linear) case of eq If fa = 1.0 (i.e.
complete absorption) and a>>1 (i.e. strongly dissolution rate-
limited absorption), then Fa = Fd.
This IVIVR analysis has been applied to several formulations of
metoprolol, piroxicam, and ranitidine .
The use of the term IVIVR rather than IVIVC is preferred.
IVIVR
117. IVIVM
The objective of dissolution testing is to achieve predictability
of testing based on (co)relationship.
Differences/similarity in vitro should be reflected in vivo and
vice versa under the same testing conditions/ environment
whether products are from same lot, different formulation, or
different products.
If one set of experimental conditions provides a matched
ranking between dissolution and in vivo profiles, then it is
considered as achieving IVIVC. The dissolution test would be
called as bio-relevant.
If none of the prior dissolution methods provide such
matching, then a new set of experimental conditions may
also be developed to match the ranking.
118. This approach is considered as In Vitro-In Vivo Matching
(IVIVM).
It is clear to see that this approach seeks to match, thus
would NOT reflect a relationship or predictability aspect,
which is the requirement of an IVIVC.
Thus, it is of limited use as compared to IVIVC.
IVIVM
119. IVIVP
The objective of IVIVC is to link or relate the in vitro
(dissolution) and in vivo (C-t) profiles.
A dissolution test is performed and then C-t profile from it is
predicted.
Therefore, it can be said that in reality the purpose of
commonly referred practices of IVIVC is to transfer a
dissolution (in vitro) to a C-t (in vivo) profile, or simply in
vitro-to-in vivo profiling.
The mathematical technique to transfer in vitro profile to in
vivo profile is known as convolution.
Convolution is relatively simpler than de-convolution as the
former can be applied using simple spreadsheet software,
e.g., MS Excel.
120. Applications of IVIVC
IVIVC plays an important role in product development:-
serves as a surrogate of in vivo and assists in supporting
biowaivers;
supports and / or validates the use of dissolution methods and
specifications; and
assists in quality control during manufacturing and selecting
appropriate formulations.
121. Applications of IVIVC
1. Biowaivers
The first and main role of establishing IVIVC is to use dissolution
test as a surrogate for human studies.
The benefit of this is to minimize the number of bioequivalence
studies performed during the initial approval process and during
the scaling-up and post-approval changes.
122. Applications of IVIVC
The FDA guidance outlines five categories of
biowaivers:
biowaivers without an
IVIVC
biowaivers using an
IVIVC: non-narrow
therapeutic index
drugs
biowaivers using an
IVIVC: narrow
therapeutic index
drugs
biowaivers when in
vitro dissolution is
independent of
dissolution test
conditions
situations for which an
IVIVC is not
recommended for
biowaivers
123. Applications of IVIVC
Biowaivers Without IVIVC
Biowaivers for the changes made on lower strengths are
possible without an IVIVC if -
all strengths are compositionally proportional or qualitatively
the same,
in vitro dissolution profiles of all strengths are similar,
all strengths have the same release mechanism,
bioequivalence has been demonstrated on the highest
strength (comparing changed and unchanged drug product),
and
dose proportionality has been demonstrated for this ER drug
product.
124. Applications of IVIVC
For these situations, waivers can be granted without an
IVIVC if dissolution data are submitted in the
application/compendial medium and in three other media
(e.g., water, 0.1N HCl, and USP buffer at pH 6.8).
125. Applications of IVIVC
Biowaivers based on IVIVC
For generic products to qualify for biowaiver, based on
IVIVC , one of the following situations should exist:
Bioequivalence has been established for all strengths of
the reference listed product.
Dose proportionality has been established for the
reference listed product, and all reference product
strengths are compositionally proportional or
qualitatively the same, have the same release mechanism,
and the in vitro dissolution profiles of all strengths are
similar.
126. Applications of IVIVC
Bioequivalence is established between the generic product
and the reference listed product at the highest and lowest
strengths and, for the reference listed product, all strengths
are compositionally proportional or qualitatively the same,
have the same release mechanism, and the in vitro
dissolution profiles are similar.
127. Applications of IVIVC
2. Establishment of dissolution specifications
In vitro dissolution specifications should generally be based on
the bioavailability performance of the lots. This approach is
based on the use of the in vitro dissolution test as a quality
control test.
An IVIVC adds in vivo relevance to in vitro dissolution
specifications, beyond batch-to-batch quality control.
In this approach, the in vitro dissolution test becomes a
meaningful predictor of in vivo performance of the formulation,
and dissolution specifications may be used to minimize the
possibility of releasing lots that would be different in in vivo
performance.
128. Applications of IVIVC
Major drawback in the widespread use of IVIVC is that this
approach is product dependent.
The IVIVC cannot be used across the products, especially drug
product with different release mechanisms .
E.g. in the case of controlled release drug delivery systems .
129. Softwares Used in IVIVC
IVIVC
Software
WinNonli
n- IVIVC
Toolkit
GastroPlus
v. 6.1
IVIVCPlus
PDx-
IVIVC
DDDPlus
v. 3.0
ivivc for
R
Kinetica