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Definition: It refers to the establishment of rational relationship between a biological response produced

by a dosage form and a physico chemical characteristics.

1. Quality control procedures

2. Tablet or Capsule disintegration

3. Instrumental methods of analysis

Dissolution Rate Test•The rate of drug absorption•Dissolution Profile Parameters•In Vivo Performance•Proper In-Vitro Dissolution Rate - Correlate the data with the bioavailability•Buffer Solutions

ApparatusSpeed of RotationTemperaturepHSamplesDissolution MediaSampling timePercent coefficient

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Important Purpose1.Providing necessary process control

2.Determing stability of dosage form3.Facilitatinmg certain regulatory

determinations

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 time2.Apparent rate constant for elimination3.Biological half life4. Urinary excretion rate and amount excreted in urine at infinity

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

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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 surrvogate for invivo performance of formulations and no additional human studies are needed to justify changes in manufacturing site raw material are minor formulation changes.

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.

1. It does not reflect the complete shape of plasma level curve which is the critical factor that defines the performance of control release/sustained release product

2. The correlation is non unique . Thus it can only serve as a guide in formulation development and as a qulaty control procedure.

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% dissolutionTransform T to the corresponding invitro time point applying the equation T= invivo time/intensity factor.

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In-Vitro

Dissolution testing of product to asses release rates under various conditions.

Plasma Level Data: It is established both for a batch of material.

1.Predictive Mathematical Model2.Quality control tool.3.Series of Dosage forms.

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Batch to Batch consistency.Development of new dosage form.Assisting validity.

Two Basic Approches:

Establishing a Relationship.Data form previous bio-availability.

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Advantages

It reflects complete plasma level curve.

Method of manufacturing raw material supplies.

Extremes of Q.C standards can be justified by convolution or deconvolution procedure.

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Drug or Product Requirements for anIVIVC

• Caution, if narrow therapeutic range

• Linear pharmacokinetics

• Preferably BCS I or II

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Data Requirements

In vitro data

• data from batches tested in vivo

• compendial method (justify other method)

• aqueous medium, n ≥ 12 (!), CV < 10%

• profiles of test products of the same type curve

• (difference factor f1, similarity

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Data Requirements

In vivo data

• data from study in humans, n ≥ 6, fasted

• cross-over design

• formulations with different release rates

• reference formulation (solution, i.v. bolus)

• same moiety as measured in vitro

• (biobatch)

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Mathematical Techniques

Assessment of in vivo drug release or absorption from plasma profiles:

• Model-dependantbased on the mass balance among the pharmacokineticcompartments(e.g. Wagner-Nelson, Loo-Riegelman)

• Model-independantbased on Theory of Linear System Analysis(Convolution / Deconvolution)

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Purpose of IVIVC and BCS

Reduction of regulatory burden: IVIVC in lieu of additional in vivo experiments, leading to Time/Cost savings during product developmentScale-up, post approval changesBiowaiver

Enhanced significance of in vitro testing

Justification for “therapeutic” product quality

therapeutically meaningful release specifications

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Rapid and similar dissolutionHigh SolubilityHigh permeabilityWide therapeutic windowExcipients

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Registration of Changes for Existing Productswhere a Robust IVIVC can Substitute a

Bioequivalence Study

• Level 3 Changes (U.S.) [SUPAC]

• Type II Variations (European Union)

• (Line extensions (bracketing principle))

• Exceptions exist, e.g. narrow therapeutic range drugs,nonlinear pharmacokinetics

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Specification Setting for Modified ReleaseProducts (EMEA)

• Three points (20-30%, around 50%, more than 80%)

• No IVIVC: Justify that side-batches are bioequivalentdifference upper / lower limit: up to 20%

• Specifications must be met during shelf-life of product

• IVIVC established: Predicted profiles from upper and lowerrelease limits are in 20% range of AUC

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CONCLUSION:

In recent times much efforts has gone into establishing the invitro invivo correlations for different types of control release formulations. Physico chemical propeties of the invitro environment are simulated with those invivo followed by comparision of 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.

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REFERENCES:

1.BIOPHARMACEUTICS AND PHARMACOKINETICS : D.M.BRAHMANKAR SUNIL B.JAISWAL

2.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

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Any Queries???

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THANK YOU

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