Similarity and Difference Factors in Dissolution Studies

By: Jessica FernandesReg. No. 150617004

Department of Pharmaceutics

Guided By Mr. Lalit KumarAssistant Professor-senior scale

Department of PharmaceuticsMCOPS, Manipal

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Definition

It is graphical representation [in terms of concentration vs. time] of complete release of drug 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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Importance of dissolution profile Comparison

Dissolution profile of an A.P.I. reflects its release pattern under the selected condition sets.

FDA has placed more emphasis on dissolution profile comparison in the field of post approval changes.

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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Objective of dissolution profile Comparison

• To Develop in-vitro in-vivo correlation which can help to reduce costs, speed-up product development and reduce the need to perform costly bioavailability human volunteer studies.

• 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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METHODS TO COMPARE DISSOLUTION PROFILE

Graphical method

Statistical method

t- Test ANOVA

Zero order First order Hixson-crowell law

Higuchi model

Korsemeyar and peppas model

f1 and f2 comparison

Model independent method (Pair Wise Procedure)

Model dependent methods

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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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Statistical Analysis

1. Student’s t-Test

Following tests are commonly used…a) Paired t-testb) Unpaired t-test

Calculated ‘t’ value is compared with tabulated value of ‘t’ if the calculated value exceeds the tabulated value, then the null hypothesis should be rejected and vice versa.

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2. ANOVA METHOD (Analysis of Variance)

This test is generally applied to different groups of data.

Here we compare the variance of different groups of data

and predict whether the data are comparable or not.

Minimum three sets of data are required. Here first we

have to find the variance within each individual group and

then compare them with each other.

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Model dependent methods Zero order kinetics

Qt = Q0+K0t

Where, Qt is the amount of drug dissolved in time tQ0 is the initial amount of drug in the solutionK0 is the zero order release constant expressed in units of concentration/time

.

Plot: Cumulative amount of drug released versus time.

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

100 5 10 15 20 250

10

20

30

40

50

60

70

80

90

100R² = 0.965244629183049

cum

ulat

ive

perc

ent o

f dru

g re

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ed

Time (h)

Zero order Plot:

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First order model log C = log C0 - Kt / 2.303

Where

C0 is the initial concentration of drug,

K is the first order rate constant, and

t is the time.

Plot: log concentration of drug remaining vs. time which would yield a straight line with a slope of -K/2.303.

Application: This relationship can be used to describe the drug dissolution in pharmaceutical dosage forms such as those containing water soluble drugs in porous matrices.

120 5 10 15 20 25 3094

95

96

97

98

99

100

101

R² = 0.933289601784183L

og c

once

ntra

tion

Time (h)

First order plot

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Higuchi model (Diffusion matrix formulation)

• This is given by Higuchi.

Where Q is the amount of drug released in time‘t’ per unit area, K is higuchi constant T is time in hr.

Plot: The data obtained is to be plotted as cumulative percentage drug release versus Square root of time.

Application:modified release pharmaceutical dosage forms, transdermal systems and matrix tablets with water soluble drugs.

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Hixson-Crowell model

Hixson and Crowell described this Where W0 is the initial amount of drug Wt is the remaining amount of drug at time t .

 Plot: Data is to be plotted as cube root of drug percentage remaining in matrix versus time.

Application: This expression applies to pharmaceutical dosage form such as tablets, where the dissolution occurs in planes that are parallel to the drug surface if the tablet dimensions diminish proportionally in such a manner that the initial geometrical form keeps constant all the time.

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Korsmeyer - Peppas modelThe KORSEMEYER AND PEPPAS described this method.. It is given by the equation : Mt /M∞ = Ktn where Mt / M ∞ is fraction of drug released t = time K=constant includes structural and geometrical characteristics

of the dosage form n= release component which is indicative of drug release

mechanism where , n is diffusion exponent.

If n= 1 , the release is zero order . n = 0.5 the release is best described by the Fickian diffusion 0.5 < n < 1 then release is through anomalous diffusion or case

two diffusion. In this model a plot of percent drug release versus time is linear.

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Model Independent ApproachMoore and Flanner proposed a model independent mathematical approach to compare the dissolution profile using two factors, f1 and f2.

1. Difference Factor

The difference factor (f1 ) calculates the percent (%) difference between the two curves at each time point and is a measurement of the relative error between the two curves:

f1= {[Σ t=1n |R-T|] / [Σ t=1

n R]} ×100

where n is the number of time points, R is the dissolution value of the reference (prechange) batch at time t, and T is the dissolution value of the test (postchange) batch at time t.

Applications

• F1 is specially used to compare two dissolution profiles, being necessary to consider one of them as the reference standard product.

• It can measure the percent of error between two curves over all time points.

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The similarity factor (f2 ) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves.

f2= 50×log {[1+ (1/n) Σ t=1n (R-T) 2]-0.5 ×100

2. Similarity Factor

PARAMETERS VALUES

Difference Factor (f1) 0 – 15

Similarity Factor (f2) 50-100

Applications

• This method is more appropriate when more than three or four dissolution time points are available.

• The f2 may become invariant with respect to the location change and the consequence of failure to take into account the shape of the curve and the unequal spacing between sampling time points lead to errors.

• Nevertheless, with a slight modification in the statistical

analysis, similarity factor would definitely serves as an efficient tool for reliable comparison of dissolution profiles.

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Advantages1. They are easy to compute.2. They provide a single number to describe the comparison

of dissolution profile data.

Disadvantages 3. The values of f1 and f2 are sensitive to the number of

dissolution time points used.4. The basis of the criteria for deciding the difference or

similarity between dissolution profile is unclear.

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Conclusion Graphical method is first step in comparing dissolution

profile and it is easy to implement but it is difficult to make

definitive conclusions.

Various model dependent methods can be used to compare

the dissolution profile but selecting the model, interpretation

of model parameters and setting similarity limit is difficult.

f1 and f2 comparison is easy and this is most widely used

method to compare dissolution profiles. This is also

recommended by FDA.

By using all the above given models we can compare

dissolution profile of drug.

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References

1. Hussain L, Ashwini D, Sirish D. Kinetic modelling and

dissolution profiles comparison: an overview. Int J Pharm

Bio Sci. 2013; 4(1): 728 - 737.

2. Thomas O’H, Adrian D, Jackie B and John D. A review of

methods used to compare dissolution profile

data. PSTT. 1998; 1(5): 214-223.

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3. U.S. Department of Health and Human Services Food and

Drug Administration Centre for Drug Evaluation and

Research (CDER). Guidance for industry dissolution testing

of immediate release solid oral dosage forms. http://

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070237.pdf

. Accessed on 15 November 2015.

4. Jignesh A, Maulik P, Sachi P. Comparison of dissolution

profile by model independent & model dependent methods.

http://

pharmaquest.weebly.com/uploads/9/9/4/2/9942916/comparison_of_dissolution_profile.pdf

. Accessed on 15 November 2015.

Thank You