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A DoE/QbD Model for “Sweetener:Flavor:Color” Ratio Optimization

using D-Optimal Mixture Design For Development of Liquid Oral
Dosage Forms

Article  in  International Journal of Pharmaceutics · July 2015

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Shivang Chaudhary
National Institute of Pharmaceutical Education and Research
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 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE

A DoE/QbD CASE STUDY FOR

OPTIMIZATION OF SWEETENER FLAVOR
COLOR RATIO IN LIQUID ORAL MIXTURES
FOR SOLUTION/SUSPENSION DOSAGE FORM DEVELOPMENT AS PER QbD

Designed & Developed by

SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics), Ph.D. (Pharmaceutical Sciences), LSSMBB, EDMP (PM), PGDPL
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
 +91 -9904474045, +91-8866327899
 [email protected]
 www.qbdexpert.com

© Created & Copyrighted by Shivang Chaudhary.

 FACTORIAL
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SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOW
HOW TO TO
HOWSELECT
HOW
HOW
TO
HOW
IDENTIFY TO
SELECT
TO
HOW
TO
SELECT
DIAGNOSE
INTERPRET
TO CREATE
HOW TO VERIFY
RISK DESIGN?
FACTORS?
EFFECT
MODEL
MODEL?
RESIDUALS?
TERMS?
OVERLAY
GRAPHS?
DESIGN PLOT
SPACE
? ?

RISKS

UNACCEPTABLE TASTE OF LIQUID ORAL MIXTURE

PATIENT ACCEPTANCE
COMPROMISED

FACTORS

3 COLORANT

2 FLAVOR

1 SWEETENER

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
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SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOW TO
HOWHOWHOW
HOW
TO
HOW
IDENTIFY
TO TO
SELECT
SELECTTO
HOW
TO
SELECT
DIAGNOSE
INTERPRET
TO CREATE
HOW TO VERIFY
DESIGN?
EFFECT
FACTORS? MODEL
MODEL?
RESIDUALS?
TERMS?
OVERLAYGRAPHS?
DESIGN PLOT
SPACE? ?

OBJECTIVE of the experiment & NUMBERS of the factors involved were the
primary two most important factors required to be considered during selection of any design for experimentation.
OBJECTIVE To Optimize Sweetener : Flavor : Color ratio of Liquid Orals

NO. OF COMPONENTS 3 EXPERIMENTAL DESIGN SELECTED

D-OPTIMAL MIXTURE DESIGN

SWEETENER • During Optimization of sweetener, flavor & color in
liquid orals; ultimate response to be measured was
Patient Acceptability Score which was a function of
proportion of all 3 components in combination
• All 3 factors were components of a mixture, their
operating ranges were not same but their total
must be 2.0 %w/w of formulation & there were
upper bound constraints on the component
proportions in the formulation mixture
• Thus, Constrained Mixture Design is selected, in
opposite to Simplex Mixture, as a special class of
RSM for optimization of proportions especially
applicable when there are upper or lower bound
constraints on the component proportions.
A TOTAL NO OF EXP RUNS (TRIALS) 16

Factors (Variables) Lower Levels Higher Levels

A SWEETENER (%w/w) 1.00% 1.50%
B FLAVOR (%w/w) 0.50% 1.00%
C COLOR (%w/w) 0.00% 0.50%

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
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SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOWHOW TOHOW
SELECT
HOW
HOW
TO IDENTIFY
HOW TO TO
TO
HOW
TO
SELECT
DESIGNDIAGNOSE
INTERPRET
TO CREATE
HOW TO VERIFY
DESIGN?
EXPERIMENTS?
FACTORS? MODEL
MODEL?
RESIDUALS?
OVERLAYGRAPHS?
DESIGN PLOT
SPACE? ?

Here, Other Qualitative & Quantitative Formulation Composition & Mixing process was kept constant
except organoleptics for all 10 experiments i.e. Drug (5%w/w), Polysorbate 80-Surfactant-0.5%w/w, Methyl Paraben-
Antimicrobial-0.2%w/w, Ascorbic Acid-Antioxidant, & Organoleptic Additives dissolved in Ethanol (5%w/w)
were added in Purified Water-Vehicle with continuous stirring with a Batch Size of 5 liter
in a Mixer (10 liter) & mixing was continued with propeller type impeller
for 45 minutes at medium speed.
CMAs CQAs

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOW
HOW TO TO
HOWSELECT
HOW
TO
HOW
IDENTIFY
HOW SELECT
TOTO
HOW
TODIAGNOSE
INTERPRET
TO CREATE
HOW
SELECT TO VERIFY
DESIGN?
EFFECT
FACTORS? MODEL?
MODEL
RESIDUALS?
TERMS?
OVERLAY
GRAPHS?
DESIGN PLOT
SPACE? ?

During Selection of order of polynomial: MODEL (A mathematical relationship between factors & response\
assisting in calculations & predictions) for Analysis of Response; ANOVA was carried out thoroughly for
testing of SIGNIFICANCE of every possible MODEL (p<0.05), insignificant LACK OF FIT (p>0.1)
with response surface to confirm expected shape of response behavior
Sequential MODEL Sum of Square Tables

P-Value < 0.05 (Significant)  P-Value > 0.10 (Insignificant) 

Sequential model sum of square provides a sequential comparison of models showing the statistical significance of
ADDING new model terms to those terms already in the model. Thus, the highest degree quadratic model
having p-value (Prob > F) that is lower than chosen level of significance (p = 0.05)
LACK of Fit Tests

P-Value < 0.05 (Significant)  P-Value > 0.10 (Insignificant) 

Lack of Fit is the variation of the data around the fitted model. If the model does not fit the actual response
behavior well, this will be significant. Thus those models could not be used as a predictor of the response.
OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN
LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOWHOW
TO TO
HOWHOW
SELECT
TO
HOW
IDENTIFY
IDENTIFICATIONTO
SELECT
DESIGNING
HOW HOW
SELECT
TO
TOOFINTERPRET
TOOF
HOW CREATE
TO VERIFY
DIAGNOSE
ANALYSIS
DEVELOPMENT OF
DESIGN?
OFEFFECT
FACTORS? MODEL?
FACTORSMODEL
TERMS?
OVERLAY
EXPERIMMENTS GRAPHS?
DESIGN
MODEL?
RESPONSES
DESIGN PLOT
SPACE
SPACE ? ?

Numerical Analysis of Model Variance was carried out to confirm or validate that the MODEL ASSUMPTIONS for
the response behavior were met with actual response behavior or not, via testing of significance of each MODEL TERMs
with F Value >>1 & p<0.05 (less than 5% probability that a “Model F Value” this large could occur due to noise),
insignificant LACK OF FIT (p>0.10), adequate PRECISION > 4, R2 Adj & R2 Pred in good agreement <0.2d, with
well behaved RESIDUALS analyzed by diagnostic plots as GRAPHICAL INDICATORS.

Response: Angle of Repose

PREDICTION EFFECT EQUATION OF INDIVIDUAL RESPONSE BY 3rd ORDER REDUCED SPECIAL CUBIC MODEL

Patient Acceptability Score= +3.79A+3.19B+2.67C+2.57AB+4.73AC+1.94BC+15.05ABC

Residual (Experimental Error) Noise = (Observed Responses) Actual Data– (Predicted Responses) Model Value
During RESIDUAL ANALYSIS, model predicted values were found higher than actual & lower than actual with equal probability in Actual
Vs Predicted Plot. In addition the level of error were independent of when the observation occurred in RESIDUALS Vs RUN PLOT, the size of the
observation being predicted in Residuals Vs Predicted Plot or even the factor setting involved in making the prediction in Residual Vs Factor Plot

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOW
HOW TO TO
HOW
HOW
SELECT
HOW
TOHOW
IDENTIFYTO
SELECT
TO
HOW
SELECT
DIAGNOSE
TO TO CREATE
HOW TO VERIFY
INTERPRET
DESIGN?
EFFECT
FACTORS? MODEL
MODEL?
TERMS?
OVERLAYGRAPHS?
RESIDUALS?
DESIGN PLOT
SPACE? ?

Model Graphs gives a clear picture of how the response will behave at different levels of factors at a time in 2D, 3D & 4D
Response: Angle of Repose
2 Components Mix Plots

Contour Plot Response Surface

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOW
HOW TO TO
HOW
HOW
SELECT
HOW
TO
HOW
IDENTIFYTO
SELECT
TO
SELECT
TODIAGNOSE
HOW INTERPRET
HOW TO VERIFY
TO DEVELOP
DESIGN?
EFFECT
FACTORS? DESIGN
MODEL?
MODEL SPACE?
RESIDUALS?
TERMS?
GRAPHS?
DESIGN SPACE?

Responses (Effects) Goal for Individual Responses

Y1 PATIENT ACCEPTANCE To achieve maximum Patient Acceptance Score as maximum as possible out of 10. &
SCORE NLT 4.5 out of 5.0
By Overlaying contour maps from each responses on top of each other, RSM was used to find out the IDEAL “WINDOW”
of operability-Design Space per proven acceptable ranges & Edges of Failure with respect to ultimate goals

Factors (Variables) Knowledge Space Design Space Control Space

A SWEETENER (%w/w) 1.00-1.50% 1.10-1.35% 1.15-1.30%
B FLAVOR (%w/w) 0.50-1.00% 0.52-0.76% 0.60-0.70%
C COLOR (%w/w) 0.00-0.50% 0.05-0.25% 0.10-0.20%

OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN

LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 FACTORIAL
RESPONSEMIXTURE
SURFACE

SIMPLEX SIMPLEXD-OPTIMAL
LATTICECENTROIDMIXTURE
HOWHOW
TO TO
HOWHOW
SELECT
HOW
TO
HOW
IDENTIFY
IDENTIFICATIONTO
SELECT
TO
DESIGNINGHOW
SELECT
TODIAGNOSE
OFINTERPRET
TOOF
HOW
ANALYSIS CREATE
TO VERIFY
DEVELOPMENT OF
DESIGN?
EFFECT
FACTORS?
OF MODEL?
FACTORSMODEL
RESIDUALS?
TERMS?
OVERLAY
EXPERIMMENTS GRAPHS?
DESIGN
RESPONSES
DESIGN PLOT?
SPACE?
SPACE

After completion of all experiments according to DoE, Verification was required TO CONFIRM DESIGN SPACE developed by
selected DESIGN MODEL, which should be rugged & robust to normal variation within a SWEET SPOT in OVERLAY PLOT,
where all the specifications for the individual responses (CQAs) met to the predefined targets (QTPP)
SWEETENER (%) FLAVOR (%) COLOR (%)

1.00-1.50 0.50-1.00 0.00-0.50 Known Ranges of

OPERABILITY
KNOWLEDEGE SPACE before Designing
1.10-1.35 0.52-0.76 0.05-0.25 Optimized Ranges of
FEASIBILITY
DESIGN SPACE after Development
1.15-1.30 0.60-0.70 0.10-0.20 Planned Ranges of
CONTROLLING
CONTROL SPACE during Commercialization

The OBSERVED EXPERIMENTAL RESULTS of 3 additional confirmatory runs across the entire design space were
compared with PREDICTED RESULTS from Model equation by CORRELATION COEFFICIENTs. In the case of all
3 responses, R2 were found to be more than 0.900, confirming right selection of DESIGN MODEL.
OPTIMIZATION OF SWEETENER: COLOR: FLAVOR RATIO IN
LIQUID ORAL(SOLUTION/ SUSPENSION/ EMULSION) DOSAGE FORM © Created & Copyrighted by Shivang Chaudhary.
 Designing is a Journey of Discovery…

© Created & Copyrighted by

SHIVANG CHAUDHARY
Chief Knowledge Officer (CKO) & Global Head Quality by Design at QbD Expert™
MS (Pharmaceutics), Ph.D. (Pharmaceutical Sciences), LSSMBB, EDMP (PM), PGDPL
www.facebook.com/QbDExpert www.linkedin.com/groups/8264051
 +91 -9904474045, +91-8866327899
 [email protected]
 www.qbdexpert.com

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