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COMPARISON OF DISSOLUTION PROFILE BY DIFFERENT METHODS

& IVIVC

Presented ByMr.Akash GujarathiM.Pharm 1st semDept. of Pharmaceutics

Poona College Of Pharmacy,Centre of Advanced Research In

Pharmaceutical Sciences

Guided ByDr. Mrs. V.B. Pokharkar,Vice Principal and Head Of Department of Pharmaceutics

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CONTENTS…. Definition Objectives Importance Different methods used for dissolution comparison Comparison of different methods IVIVC References

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DEFINITION:

It is graphical representation [in terms of concentration vs. time] of complete release of A.P.I. from a dosage form in an appropriate selected dissolution medium.

i.e. in short it is the measure of the release of A.P.I from a dosage form with respect to time.

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OBJECTIVE: To Develop invitro-invivo correlation which can help to

reduced costs, speed-up product development and reduced the need of perform costly bioavailability human volunteer studies.

Demonstrating equivalence after change in formulation of drug product

Establish the similarity of pharmaceutical dosage forms, for which composition, manufacture site, scale of manufacture, manufacture process and/or equipment may have changed within defined limits.

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IMPORTANCE OF DISSOLUTION PROFILE Dissolution profile of an A.P.I. reflects its release pattern

under the selected condition sets. i.e. either sustained release or immediate release of the formulated formulas.

For optimizing the dosage formula by comparing the dissolution profiles of various formulas of the same A.P.I

The most important application of the dissolution profile is that by knowing the dissolution profile of particular product of the BRAND LEADER, we can make appropriate necessary change in our formulation to achieve the same profile of the BRAND LEADER.

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METHODS TO COMPARE DISSOLUTION PROFILE

Grafical Method

Statistical Analysis

Model Dependent

Method

Model Independent

Method

Zero order

First order

Hixson-crowell

Higuchi model

Korsemeyar and

peppas model

Baker-Lonsdale model

Ratio Test

Procedure

Pair Wise Procedure-(f1andf2)

Multivariate Confidence

regionProcedure

t Test ANOVA

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GRAPHICAL METHOD In this method we plot graph of Time V/S concentration of

solute (drug) in the dissolution medium or biological fluid.

The shape of two curves is compared for comparison of dissolution pattern and the concentration of drug at each point is compared for extent of dissolution.

If two or more curves are overlapping then the dissolution profile is comparable.

If difference is small then it is acceptable but higher differences indicate that the dissolution profile is not comparable.

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GRAPHICAL COMPARISON OF DISSOLUTION PROFILE

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MODEL DEPENDENT METHODS1) Zero order kinetics (osmotic

system ,transdermal system) Zero order A.P.I.release contributes drug release from

dosage form that is independent of amount of drug in delivery system. ( i.e., constant drug release)i.e.,

A0-At = kt

Where ,A0 = initial amount of drug in the dosage form;

At = amount of drug in the dosage form at time‘t’ k = proportionality constant

Application: Transdermal systems as well as matrix tablets with low solubility drugs in coated forms, osmotic systems.etc

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2) FIRST ORDER KINETICS (WATER SOLUBLE DRUGS IN POROUS MATRIX) Using Noyes Whitney’s equation, the rate of loss of drug from

dosage form (dA/dt) is expressed as; -dA/dt = k (Xs – X) Assuming that,

sink conditions = dissolution rate limiting step for in-vitro studyabsorption = dissolution rate limiting step for in-vivo study.

Then (1) turns to be: -dA/dt = k (Xs ) = constant So it becomes,

A = Ao × e-k

Applications: This relationship can be used to described the drug dissolution in phaarmaceutical dossage forms containing water soluble drugs in porous matrices

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3)HIGUCHI MODEL (DIFFUSION MATRIX FORMULATION) Higuchi in 1961 developed models to study the release of water

soluble and low soluble drugs incorporated in semisolid and solid matrices.

To study the dissolution from a planer system having a homogeneous matrix the relation obtained was;

A = [D (2C – Cs)Cs × t]1/2

Where A is the amount of drug released in time‘t’ per unit area, C is the initial drug concentration, Cs is the drug solubility in the matrix media D is the diffusivity of drug molecules in the matrix substance.

Applications: Modified release dossage forms, transdermal systems and matrix tablets with water soluble drugs

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4) BAKER-LONSDALE MODEL(MICROSPHERES , MICROCAPSULES) In 1974 Baker-Lonsdale (Baker and Lonsdale, 1974) developed the

model from the Higuchi model and describes the controlled release of drug from a spherical matrix that can be represented as:

3/2 [1-(1-At/A∞)2/3]-At/A∞ = (3DmCms) / (r02C0) X t

Where At is the amount of drug released at time’t’ A∞ is the amount of drug released at an infinite time,

Dm is the diffusion coefficient,

Cms is the drug solubility in the matrix,

ro is the radius of the spherical matrix

Co is the initial concentration of the drug in the matrix.

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5) HIXON – CROWELL MODEL (ERODIBLE MATRIX FORMULATION) To evaluate the drug release with changes in the surface area

and the diameter of the particles /tablets The rate of dissolution depends on the surface of solvent -

the larger is area the faster is dissolution. Hixon-Crowell in 1931 ( Hixon and Crowell, 1931) recognized

that the particle regular area is proportional to the cubic root of its volume, desired an equation as

Wo1/3-W1/3 = K × t

where, Wo= original mass of A.P.I.particles

K = cube-root dissolution rate constant W = mass of the A.P.I at the time ‘t’ This model is called as “Root law”.

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GUIDANCE FOR INDUSTRYTo allow application of these models to comparison of dissolution profiles, the following procedures are suggested:

1. Select the most appropriate model for the dissolution profiles from the standard, prechange, approved batches. A model with no more than three parameters (such as linear, quadratic, logistic, probit, and Weibull models) is recommended.

2. Using data for the profile generated for each unit, fit the data to the most appropriate model.

3. A similarity region is set based on variation of parameters of the fitted model for test units (e.g., capsules or tablets) from the standard approved batches.

4. Calculate the MSD (Multivariate Statistical Distance) in model parameters between test and reference batches.

5. Estimate the 90% confidence region of the true difference between the two batches.

6. Compare the limits of the confidence region with the similarity region. If the confidence region is within the limits of the similarity region, the test batch is considered to have a similar dissolution profile to the reference batch.

MODEL INDEPENDENT METHODS PAIRED WISE PROCEDURE

DIFFERENCE FACTOR (f1) & SIMILARITY FACTOR (f2) The difference factor (f1) as defined by FDA calculates the %

difference between 2 curves at each time point and is a measurement of the relative error between 2 curves.

f1 = × 100

where, n = number of time pointsRt = % dissolved at time t of reference product (pre change)

Tt = % dissolved at time t of test product (post change) 15

n

t

n

t

Rt

TtRt

1

1

The similarity factor (f2) as defined by FDA is logarithmic reciprocal square root transformation of sum of squared error and is a measurement of the similarity in the percentage (%) dissolution between the two curves

f2 = 50 ×

Limits for similarity and Difference factors

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100 1

log )(115.0

n

rTtRtwt

n

Difference Factor

Similarity Factor

Inference

0 100 Dissolutions profile are similar

≤15 ≥50 Similarity or equivalence of two profiles

Advantages:1. They are easy to produceThey provide single number to describe the comparison of dissolution profile data

Disadvantages:2. The values of f1 and f2 are sensitive to the number of

dissolution time point used3. If the test and reference formulation are interchanged, f2

is unchanged but f1 is not, yet difference between two mean profiles remains same

4. The basis of criteria for deciding the difference or similarity between dissolution profile is unclear

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The evaluation of similarity between dissolution profile is based on following conditions Minimum of three dissolution time points are measured Number of drug products tested for dissolution is 12 for both

test and reference Not more than one mean value of >85% dissolved for each

product Standard deviation of mean of any product should not be

more than 10% from 2nd to last dissolution time point

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RESEARCH ARTICLE:

A Comparative Study for Evaluation of Different Brands of Metformin Hydrochloride 500 Mg TabletsMarketed in Saudi Arabia

Corresponding authorSamar A. Afifi1&21 Department of Pharmaceutics, College of Pharmacy,King Saud University, Riyadh, Saudi Arabia

Life Science Journal 2012;9(4) http://www.lifesciencesite.com

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Abstract: The physicochemical equivalence of six brands of

Metformin hydrochloride tablets were determined through the evaluation of both official and non-official standards according to the USP pharmacopoeia including uniformity of weight, friability, hardness,disintegration, dissolution rate and drug content.

All the six brands evaluated in this study could be considered biopharmaceutically and chemically equivalent and therefore they can be substituted with the innovator product in clinical practice except Glucare®. Therefore, patients can safely switch from one brand to another.

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MATERIALS

Metformin hydrochloride brands having label strength of 500 mg (Table 1) were purchased from a retail pharmacy in Riyadh city, Saudi Arabia. All tests were performed within product expiration dates.

The reagents used were potassium dihydrogen orthophosphate (WINLAB chemicals, UK) and sodium hydroxide pellets (Poole BH15, UK).

All reagents used were of analytical grade. Distilled water was used throughout the work.

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EXPERIMENTAL CONDITUIONS: stimulated intestinal fluid pH 6.8 Apparatus-ERWEKA DT600 dissolution apparatus

(Heusenstamm,Germany) Volume-1000ml Temperature-37 ± 0.5 °C Speed-100 rpm Sample Withdrawing Intervals-10 min Each of the withdrawn sample was filtered with syringe filter

0.45μm, the filtrate diluted. The absorbance was measured at λ max 233nm using Uv-

visible spectrophotometer. The concentration was determined against standard solution

having a known concentration of Metformin hydrochloride RS in the same medium.

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The difference factor (f1) and similarityfactor (f2) was calculated for each local brandrespect to the reference brand (Glucophage®)equation (1) and (2), respectively.

The percentage of drug released fromGlucophage® as an innovative was comparedwith the percentage of drug released from eachbrand individually using the f1 and f2 formula

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Five generic brands of Metformin hydrochloride tablets, namely Formit® , Glucare®, Dialon®,Metaphage® and Metfor® together with the innovative (Glucophage®) have been subjected to analysis according to the monograph of USP 32 Pharmacopoeia.

The results have shown that all the tested brands satisfied the USP requirements in terms of identification, assay and dissolution.

Dissolution profiles revealed differences between the different generics. Four generic products could be said to be equivalent to the originator (Glucophage®) while the Glucare® was nonequivalent.

According to the present study patients can safely switch from one brand to another but with consulting them of the possibility of some minor GIT complications that may occur after the treatment with new alternative brand.

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Conclusion

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IN VITRO IN VIVO CORRELATION (IVIVC) In IVIVC, "C" denotes "Correlation", which means

"the degree of relationship between two variables".

IVIVC is defined as the predictive mathematical model that describes the relationship between an in-vitro property(such as rate and extent of dissolution) of dossage form and an in-vivo response (such as plasma drug concentration)

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DEFINATION The Food and Drug Administration (FDA) defines

“A predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”.

The United States Pharmacopoeia (USP) also defines

“The establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form”.

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IMPORTANCE OF IVIVC To serve as a surrogate(alternate) for in vivo bioavailability. To support biowaivers for bioequivalence testing. To validate the use of dissolution methods and set the

dissolution specifications. IVIVC proves an important research tool in the development

of drug delivery systems. The IVIVC model facilitates the rational development &

evaluation of immediate or extended release dosage forms. Hence it acts as a tool for formulation screening.

To assist quality control for certain scale-up and post-approval changes (SUPAC).

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1. CORRELATIONS BASED ON THE PLASMA LEVEL DATA:

Parameters used for correlating In Vitro Dissolution with Plasma Data

In vitro dissolution parameters In vivo plasma data parameters

Time for specific amount of drug to dissolve (e.g. 50% of the dose)Amount dissolved at a specific time pointMean dissolution time

Parameter estimated after modeling the dissolution process

AUC, Cmax

Fraction absorbed, absorption rate constant KaMean residence time, mean dissolution time, mean absorption timeConcentration at time t, amount absorbed at time t

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2. CORRELATION BASED ON THE URINARY EXCRETION DATA

Dissolution parameters are correlated to the amount of drug excreted unchanged in the urine, cumulative amount of drug excreted as a function of time, etc.

An acute pharmacological effect such as LD50 in animals is related to any of the dissolution parameters.

3. CORRELATION BASED ON THE PHARMACOLOGICAL ACTION

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FACTORS AFFECTING IVIVC

Complexity of the delivery

system.Composition of

formulation.

Physicochemical properties of

drug.Dissolution

method

Method of manufacture

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BASIC DEFINATIONS ABOUT IVIVC

• The mean time for which the drug resides in the body. Also known as mean transit time. • MRT = AUMC / AUC• where, AUMC = Area under first moment Curve (Concentration*time Vs time)• AUC = Area under curve (Concentration Vs time)• Both AUMC & AUC can be obtained by using Trapezoidal rule.

Mean Residence Time:

• The mean time required for drug to reach systemic circulation from the time of drug administration.

• MAT = MRT oral – MRT i.v.

Mean Absorption Time:

• It reflects the mean time for drug to dissolve in-vivo. For solid dosage form: • MDT solid = MRT solid – MRT solution

Mean In-vivo Dissolution Time:

• % PE = [(Observed value – Predicted value) / Observed value] x 100

Percent Prediction Error:

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LEVELS OF IVIVC

Level A

• Most informative & recommended

Level B

• Least useful in regulatory purpose

Level C

• Useful for early stages of formulation development

Multiple Level C

• Useful as Level A

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It is defined as a hypothetical model describing the relationship between a fraction of drug absorbed and fraction of drug dissolved.

In order to develop a correlation between two parameters one variable should be common between them.

The data available is in vitro dissolution profile and in vivo plasma drug concentration profile whose direct comparison is not possible.

To have a comparison between these two data, data transformation is required.

It is considered as a predictive model for relationship between the entire in vitro release time courses.

Level A Level B Level C Multiple C

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Advantages: 1. A point to point correlation is developed. The in vitro dissolution curve serves as a

surrogate for in vivo performance. Any change in manufacturing procedure or modification in formula can be justified without the need for additional human studies.

2. The in vivo dissolution serves an in vivo indicating quality control procedure for predicting dosage form’s performance.

Level A Level B Level C Multiple C

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Level B IVIVC uses the principles of statistical moment analysis. The mean in vitro dissolution time(MDTvitro) is compared either to the mean residence time (MRT) or to the mean in vivo dissolution time (MDTvivo).

Level B correlation, like a Level A, uses all of the in vitro and in vivo data, but is not considered to be a point-to-point correlation.

Level B correlation does not uniquely reflect the actual in vivo plasma level curve, because a number of different in vivo curves will produce similar mean residence time values.

MATHS TOOL : MDTvitro VS MDTvivo or

MRTvivo

Level A Level B Level C Multiple C

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In this level of correlation, one dissolution time point (t50%, t90%, etc.) is compared to on mean pharmacokinetic parameter such as AUC, t max or C max.

It represents a single point correlation and doses not reflect the entire shape of the plasma drug concentration curve.

Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected.

While the information may be useful in formulation development, biowaiver is generally not possible.

Level A Level B Level C Multiple C

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 point level C correlation may be used to justify a bio waiver, provided that the correlation has been established over the entire dissolution profile with one or more pharmacokinetic parameters of interest.

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Level A Level B Level C Multiple C

VARIOUS PARAMETERS USED IN IVIVC DEPENDING ON THE LEVEL

Level In vitro In vivo

A Dissolution curve Input (absorption) curves

B Statistical Moments: MDT

Statistical Moments: MRT, MAT

C

Disintegration time, Time to have 10, 50,

90% Dissolved, Dissolution rate,

Dissolution efficiency

Cmax, Tmax, Ka,

Time to have 10, 50, 90% absorbed,

AUC (total or cumulative)

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APPLICATIONS OF IVIVC IN DRUG DELIVERY 1. Early Stages of Drug Delivery & Development: • Proof of Concept 

2. Formulation Assessment:• In Vitro Dissolution

3. Dissolution Specifications4. Future Biowaivers5 . IVIVC – Parenteral Drug Delivery• Potent Drugs & Chronic Therapy• Limited volume of tissue fluids and Area of absorption 40

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SOFTWARES USED IN IVIVC

IVIVC Softwar

e

WinNonlin- IVIVC Toolkit GastroPlus

v. 6.1 IVIVCPlus

PDx-IVIVC

DDDPlus v. 3.0

IVIVC for R

Kinetica

REFERENCES Biopharmaceutics and Pharmacokinetics by D. M.

Brahmankar, 2nd edition 2009, page no. 432 to 434 By Madhusmruti Khandai Research article of International

Journal of Pharmaceutical Sciences Review and Research Volume 1, Issue 2, March – April 2010; Article 001

Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), August-2011

International Journal of Pharmaceutical Science Vol-1, Issue-1, page no.57-64, 2010 42

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Research Article on:A Comparative Study for Evaluation of Different Brands of Metformin Hydrochloride 500 Mg Tablets Marketed in Saudi Arabia;by-Samar A. Afifi1&2

Life Science Journal 2012;9(4) http://www.lifesciencesite.com Guidance for Industry; Extended Release Oral Dosage Forms:

Development, Evaluation, and Application of In Vitro/In Vivo Correlations. www.fda.gov/cder/guidance/index.htm

Dissolution, Bioavailability and Bioequivalence by Hamed M. Abdou, Mack Publishing House.

IVIVC: Methods and Applications in Modified-Release Product Development; Harald Rettig and Jana Mysicka. Dissolution Technologies | FEBRUARY 2008

IVIVC: An Important Tool in the Development of Drug Delivery Systems; Gangadhar Sunkara, PhD, and Dakshina M. Chilukuri, PhD. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=144

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