invitro invivo correlations

INVITRO-INVIVO CORRELATIONS : 

INVITRO-INVIVO CORRELATIONS By: N.Arun yuvaraj goud , Mpharm (pharmaceutics) 10U21S0316 Sree dattha college of pharmacy

CONTENTS: 

CONTENTS INTRODUCTION INVITRO STUDIES INVIVO STUDIES CORRELATION PROCEDURE FOR INVITRO INVIVO CORRELATIONS APPLICATIONS CONCLUSION REFERENCES

INTRODUCTION : 

INTRODUCTION Definition: It refers to the establishment of rational relationship between a biological response produced by a dosage form and a physico chemical characteristics . The IVIVC is to serve as a surrogate for in vivo bioavailability and to support biowaivers IVIVC could also be employed to establish dissolution specifications and to support and/or validate the use of dissolution methods

In Vitro Studies: 

In Vitro Studies 1. Quality control procedures 2. Tablet or Capsule disintegration 3. Instrumental methods of analysis 4. 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

INVITRO DISSOLUTION TESTING: 

Apparatus Speed of Rotation Temperature pH Samples Dissolution Media Sampling time Percent coefficient INVITRO DISSOLUTION TESTING

Other testing equipments Rotating bottle Flask stirrer Beaker method Flow through-dissolution method: 

Other testing equipments Rotating bottle Flask stirrer Beaker method Flow through-dissolution method Important Purpose 1.Providing necessary process control 2.Determing stability of dosage form

In-Vivo Studies: 

In-Vivo Studies Definition: In-vivo studies deals with the evolution of bioavailability and bio equivalence of pharmaceutical dosage forms using parameters like AUC,Cmax etc.. PARAMETERS: 1.Drug concentration in plasma at each sampling time 2.Apparent rate constant for elimination 3.Biological half life 4. Urinary excretion rate and amount excreted in urine at infinity

Pharmacokinetic parameters 1. Mean Residence Time(MRT) 2. Mean Absorption Time(MAT) 3.Cmax/AUC 4.The Peak Occupancy Time(POT) 5.Multiple Dosing 6.Co-efficient of variation: 

Pharmacokinetic parameters 1. Mean Residence Time(MRT) 2. Mean Absorption Time(MAT) 3.Cmax/AUC 4.The Peak Occupancy Time(POT) 5.Multiple Dosing 6.Co-efficient of variation

Correlation:: 

Correlation: Correlation is a measure of relationship between two mathematical variables or measured data values, which includes the Pearson correlation coefficient as a special case.

Levels of Correlation 1.Level A It is a point –point relationship between in-vitro data and in-vivo input rate of drug from dosage form : 

Levels of Correlation 1.Level A It is a point –point relationship between in-vitro data and in-vivo input rate of drug from dosage form

ADVANTAGES: 

ADVANTAGES 1.This is the highest category of relation which act as a meaningful quality control procedure predictive of invivo performance of formulation. 2. The invitro curve at stimulated dissolution conditions can serve as surrogate for invivo performance of formulations .

Level B Mean absorption time is plotted against mean dissolution time for atleast 3 different preparations MAT=MRTi.v-MRToral: 

Level B Mean absorption time is plotted against mean dissolution time for atleast 3 different preparations MAT= MRTi.v-MRToral

LIMITATIONS: 

LIMITATIONS 1.It utilizes all data but is non unique as diferent shaped absorption/dissolution curve could result in same moment value. 2. This correlation alone fails to justify formluations,modification ,manufacturing ,site change ,excipient source change etc… 3. It does not justify the extremes of qualtiy control standards.

Level C Selected parameters are correlated for 3 or more preparations Eg: Time for 50% dissolution vs AUC,Cmax or Tmax: 

Level C Selected parameters are correlated for 3 or more preparations Eg : Time for 50% dissolution vs AUC,Cmax or Tmax

MULTIPLE-LEVEL C CORRELATION: 

MULTIPLE-LEVEL C CORRELATION A multiple level C correlation relates one or several pharmacokinetic parameters of interest (Cmax, AUC, or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile . A multiple level C correlation be used to justify a biowaiver. A multiple Level C correlation should be based on at least three dissolution time points covering the early, middle, and late stages of the dissolution profile.

Level D: 

Level D 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

Slide 17: 

Methodology for developing the Correlation: Develop formulation with different release rate such as slow,medium,fast or a single rate if dissolution is independent. Invivo conc. Of plasma BA studies i.e., Wagnernelson method. The intensity factor = time for 50% absorption/ time for 50% dissolution Transform T to the corresponding invitro time point applying the equation T= invivo time/intensity factor. Stereochemistry and First pass effect are the factors for developing correlation

Procedure for In-Vitro in-vivo correlation In-Vivo 1.Administer the drug as an oral solution 2.Administer the drug in 3 formulation 3.Apply numericall de conversions: 

Procedure for In-Vitro in-vivo correlation In-Vivo 1.Administer the drug as an oral solution 2.Administer the drug in 3 formulation 3.Apply numericall de conversions In-Vitro Dissolution testing of product to asses release rates under various conditions.

The correlation: 

Plasma Level Data: It is established both for a batch of material. 1.Predictive Mathematical Model 2.Quality control tool. 3.Series of Dosage forms. The correlation

Slide 20: 

Drug or Product Requirements for an IVIVC • Caution, if narrow therapeutic range • Linear pharmacokinetics • Preferably BCS I or II

Slide 21: 

Mathematical Techniques Assessment of in vivo drug release or absorption from plasma profiles: Model-dependant based on the mass balance among the pharmacokinetic compartments (e.g. Wagner-Nelson, Loo-Riegelman) Model-independant based on Theory of Linear System Analysis (Convolution / Deconvolution)

Slide 22: 

Purpose of BCS(BIOPHARMACEUTICAL CLASSIFICATION SYSTEM) Time/Cost savings during product development Scale-up, post approval changes of Biowaiver. Table 1: IVIVC expectations for immediate release products based on BCS (from ref. 6 with modification) 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

APPLICATIONS: 

APPLICATIONS Batch to Batch consistency. Development of new dosage form. Assisting validity. Biowaiver for minor formulations and process changes. Establishing a Relationship. Establishment of dissolution specifications Two Basic Approches:

Slide 24: 

CONCLUSION: In recent times much efforts has gone into establishing the invitro invivo correlations for different types of control release formulations. Physico chemical properties of the invitro environment are simulated with those invivo followed by the invitro release profiles with the invivo absoprtion profile. The development of control release dosage forms has been a major step forward for therapy. However, the challenge of overcoming the vagaries of the gastro intestinal tract exists.

Slide 25: 

REFERENCES: BIOPHARMACEUTICS AND PHARMACOKINETICS : D.M.BRAHMANKAR SUNIL B.JAISWAL PRINCIPLE AND APPLICATIONS OF BIOPHARMACEUTICS AND PHARMACOKINETICS Dr.H.P.TIPNIS Dr.AMRITA BAJAJ 3. In VIVO HYDRAULIC CONDUCTIVITY OF MUSCLE El Rasheid Zakaria, Joanne Lofthouse, and Michael F. Flessner 4. BIOPHARMACEUTICS AND PHARMACOKINETICS : Venkateshwarlu 5 Chen, J.C., M.H. Chiu, R.L. Nie, G.A. Cordell, and S.X. Qius. Cucurbitacins and cucurbitane glycosides: structures and biological activities . Nat Prod Rep , 22(3): 386-99 2005

Slide 26: 

THANK YOU