IN VIVO-IN VITRO CORRELATION

Submitted By: Bhupinder Kaur

CONTENTSConceptsBCS ClassificationIVIVC ApproachesApplicationsLimitationsDissolution as serrogate to immediate release formulations Dissolution as serrogate to extended release formulations

Concepts and IntroductionIn Vivo In Vitro correlation is defined as the predictive mathematical model that describes the relationship between an in vitro property (such as rate and extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration) USP defines IVIVC as the establishment of a relationship between a biological property produced from a dosage form and a physiochemical property of the same dosage form.

Applications of IVIVCI. To ensure batch to batch consistency in the

physiological performance of a drug product by use of such in vitro values

II. To serve as a tool in the development of a new dosage form with desired in vivo performance

III.To assist in validating or setting dissolution specifications i.e. the dissolutions specifications are based on the performance of product in vivo

IV. It minimizes the number of bioequivalence studies performed during the initial approval process and during scaling up and post approval changes

V. It assists in validating dissolution specificationsVI. Biowaiver for minor formulation and process changes

Limitations of IVIVCI. The IVIVC is limited to a certain drug product.

It can be used only on that particular formulation

II. The IVIVC cannot be used on the products with different release mechanisms

Quantitative In Vitro In Vivo CorrelationA. Correlation based on the plasma level data: Parameters used for correlating in vitro dissolution with plasma

dataIn vitro dissolution parameters In vivo plasma drug parameters

Time for specific amount of drug to dissolve

AUC, Cmax

Amount dissolved at a specific time point

Fraction absorbed, absorption rate constant Ka

Mean dissolution time Mean residence time, mean dissolution time, mean absorption time

Parameter estimated after modelling the dissolution process

Concentration at time t , amount absorbed at time t

B. Correlations based on the urinary excretion data: Parameters such as amount of drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time.C. Correlation based on the pharmacological response : an acute pharmacological effect such as LD50 in animals in related to any of the dissolution parameters.Statistical moments theory: can be used to determine the relationship such as mean dissolution time vs. mean residence time.

In Vivo In Vitro Correlation levelsLevel A :

It shows relationship between fraction absorbed and fraction dissolved. No direct comparison is possible. It is considered as a predictive model for relationship between the entire in

vitro and in vivo response. There exists a linear correlation 1:1. There is point to point relationship. It is highest level of correlation and most preferred to achieve.

1 2 3 405

10152025

Level A Correlation

Fraction dissolvedFrac

tion

abs

orbe

d

Level B: In this the mean in vitro dissolution time is compared with

mean in vivo residence time or mean in vivo dissolution time.

It is based on statistical moment analysis. It is not point to point correlation. It is least used for regulatory purposes.

1 2 3 40

2040

Level B Correlation

MDT ( in vitro)MR

T (i

n vi

vo)

Level C Correlation: It is single point correlation that is established in between

one dissolution parameter like t 50% and one of the pharmacokinetic parameters like tmax, Cmax, AUC.

It is helpful in early stages of formulation .

1 2 3 40

10

20

Level C Correlation

MDT

AU

C

Multiple level C Correlation: It reflects the relationship between one or several

pharmacokinetic parameters of interest and amount of drug dissolved at several time point of dissolution. It is similar to Level A correlation.

Level D Correlation: It is not considered useful for regulatory purpose.

Class Solubility Permeability

Absorption Pattern

Examples

1 High High Well absorbed

Diltiazem, Propanolol, Metoprolol

2 Low High Variable Nifedipine, Carbamazepine, Naproxen

3. High Low Variable Insulin, Metformin, Cimetidine

4. Low Low Poorly absorbed

Taxol, Chlorthiazide, Furosemide

The Biopharmaceutics Classification System For Drugs

Drug properties that determine BCS classification

Drug property influencing absorption Corresponding parameter

Solubility: a drug with high solubility is the one whose largest dosage strength is soluble in 250 ml or less of water over a pH range of 1-8

Dose number: It is the mass of drug divided by an uptake volume of 250 ml and the drug solubility

Dissolution rate: A drug product with rapid dissolution is the one when ≥85% of the labelled amount of drug substance dissolves within 30 minutes using USP apparatus 1 or 2 in more than 900 ml volume buffer solution.

Dissolution number : It is the ratio of mean residence time to mean dissolution time

Permeability : A drug with high permeability is the one having extent of absorption greater than 90% of the administered dose given that the drug is stable in GIT

Absorption Number: it is ratio of MRT to absorption time.

BCS for immediate release drug products and IVIVC expectations.

Class Solubility Permeability IVIVC Expectations

Possibility of predicting IVIVC from dissolution data

1 High High IVIVC expected

Yes

2 Low High IVIVC expected

Yes

3 High Low IVIVC not expected

No

4 Low Low IVIVC not expected

No

BCS for extended release drug products and IVIVC expectations

Class Solubility Permeability IVIVC Expectations

1a High and site independent

High and site independent

IVIVC Level A expected

1b High and site independent

Dependent on site and narrow absorption window

IVIVC Level C expected

2a Low and site independent

High and site independent

IVIVC Level A expected

2b Low and site independent

Dependent on site and narrow absorption window

IVIVC not expected

Va Variable Variable IVIVC not expected

Vb Variable Variable IVIVC Level A expected

BCS based Biowaiver to in vivo studies

In biowaivers the in vivo bioavailability and bioequivalence studies need not to be conducted for drug products under following circumstances:1. Rapid and similar dissolution2. High solubility3. High permeability4. Wide therapeutic window5. Excipients used in dosage form are same as those present in

approved drug product.

Dissolution As per IVIVC perspective dissolution is proposed to be a serrogate of drug bioavailability. Generally following types of apparatus are being used for conducting the dissolution studies.1. Rotating basket apparatus2. Rotating paddle type apparatus3. Reciprocating cylinder apparatus4. Flow through cell apparatus5. Paddle over disc apparatus6. Cylinder apparatus7. Reciprocating disc apparatus

The conditions such as the stirring speed, choice of apparatus, pH of medium, and temperature of medium are important for conducting dissolution profile.

Dissolution medium used are: water, simulated gastric fluid (pH1.2), intestinal fluid (pH 6.8, 7.4)buffers with pH range of 4.5 to 7.5

Water and simulated gastric fluids are used for class 1 drugs The normal test duration for immediate release is 15 to 60 minutes with a single

time point.

Compendial dissolution apparatus types and their applications

Apparatus Name Drug formulation tested Apparatus 1 Rotating basket apparatus Conventional tablets,

chewable tablets, CR Formulations

Apparatus 2 Rotating paddle FDT, Chewable tablets, capsules, CR Formulations

Apparatus 3 Reciprocating cylinder CR Formulations, chewable tablets

Apparatus 4 Flow through cell Implants, poorly soluble drugs, powders

Apparatus 5 Paddle over disc Transdermal formulations

Apparatus 6 cylinder Transdermal formulations

Apparatus 7 Reciprocating disc CR Formulations

Dissolution acceptance criteriaQ is considered as the acceptance criteria for dissolution which is defined as percentage of drug content dissolved in a given time period.

Method of comparison of dissolution profile: Dissolution can be determined by calculating difference factor f1 and similarity factor f2F1=∑(Rt-Tt)*100/∑RtF2= 50log [(1+1/n∑(Rt-Tt)(Rt-Tt)]-0.5*100 where n= number of dissolution time pointsRt = dissolution value of reference productTt= dissolution value of test drug

Comparison of dissolution profile:

Difference factor f1 Similarity factor f2 Inference 0 100 Dissolution profiles are

identical

≤15 >50 Similarity or equivalence of two profiles

The evaluation of dissolution profiles is based on following conditions:•Minimum 3 dissolution points are measured•Number of drug products tested for dissolution is 12•Not more than one mean value of more than 85% dissolved for each product•S.D should not be more than 10%

Dissolution methology for immediate release products based on BCS

BCS Class Dissolution methodology

1 Single point if NLT 85% Q in 15 minutesMultiple point if Q is less than in 15 minutes

2 Multiple point

3 Same as class 1

4 Same as class 2

Stage Number of dosage units tested

Acceptance criteria

S1 6 No dosage unit is less than Q+5%

S2 6 Average of the twelve dosage units (S1+S2) > Q% and no dosage unit is less than Q-15%

S3 12 Average of 24 dosage units (S1+S2+S3)> Q% and not more than 2 dosage units are less than Q-15% and no dosage unit is less than Q-25%

Dissolution Acceptance Criteria

Dissolution acceptance criteria for extended release

Level Number tested Acceptance criteria

S1 6 No individual value exceeds 10% dissolved

S2 6 Average of the twelve dosage units (S1+S2) is not more than 10% dissolved and no individual unit is greater than 25%dissolved

S3 12 Average of 24 dosage units (S1+S2+S3) ) is not more than 10% dissolved and no individual unit is greater than 25%dissolved

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