Factor Analysis for Dissolution

Time of Effervescent Tablets

A Designed Experiment

Niu Jinshu (2010010837)

Wu Xianyu (2010010838)
Cao Liuxing (2010010836)
Wu Yining (2010010835)
Dai Yibo (2010010833)

DOE Project Factor analysis for dissolution time of effervescent tablets

Content
Abstract ....................................................................................................................................................... 3
Experiment Background & Objectives ....................................................................................................... 3
Background ......................................................................................................................................... 3
Objectives............................................................................................................................................ 3
Experiment Design ...................................................................................................................................... 4
Initial Variable Analysis & Selection .................................................................................................. 4
Variable Table...................................................................................................................................... 4
Response Variable ....................................................................................................................... 4
Control variable ........................................................................................................................... 5
Constant variable ......................................................................................................................... 5
Noise variable.............................................................................................................................. 6
Fishbone Diagram ............................................................................................................................... 6
Full factorial design .................................................................................................................................... 7
Test matrix........................................................................................................................................... 7
Factor levels ........................................................................................................................................ 8
Conducting the experiment ......................................................................................................................... 9
Experiment operations ........................................................................................................................ 9
Snapshots of experiments .................................................................................................................. 10
Analysis and result .................................................................................................................................... 10
Experiment data ................................................................................................................................ 10
Effects of factors ............................................................................................................................... 13
Significant factors ..................................................................................................................... 13
Effect of each factor .................................................................................................................. 18
2-factor-interacion ............................................................................................................................. 20
3-factor-interacion ............................................................................................................................. 23
Regression model .............................................................................................................................. 26
Conclusion and discussion ........................................................................................................................ 27
Model validation ....................................................................................................................................... 27

Figure Content
Figure 1 Fishbone diagram of dissolution rate .................................................................................... 7
Figure 2 Snapshot of experiments ..................................................................................................... 10
Figure 3 Result cubes ........................................................................................................................ 12
Figure 4 Main effect plot for the 4 factors ........................................................................................ 13
Figure 5 Interaction plot for the 4 factors.......................................................................................... 14
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DOE Project Factor analysis for dissolution time of effervescent tablets

Figure 6 The normality plot for effects ............................................................................................. 14
Figure 7 ANOVA table ...................................................................................................................... 15
Figure 8 Reduced Model Normality plot .......................................................................................... 15
Figure 9 Half normal probability plot ............................................................................................... 16
Figure 10 Pareto plot of the reduced model ...................................................................................... 16
Figure 11 ANOVA for the reduced model ......................................................................................... 17
Figure 12 Residual plot ..................................................................................................................... 17
Figure 13 Main effect plot of flavor .................................................................................................. 18
Figure 14 Main effect plot of volume ............................................................................................... 19
Figure 15 Main Effect Plot of temperature ....................................................................................... 20
Figure 16 Interaction plot for temperature and flavor ....................................................................... 21
Figure 17 The contour plot for flavor and temperature ..................................................................... 22
Figure 18 The response surface ......................................................................................................... 22
Figure 19 Cube plot of three factor interaction ................................................................................. 23
Figure 20 The interactions between BC and D ................................................................................. 24
Figure 21 The interactions between CD and B ................................................................................. 24
Figure 22 The interactions between BD and C ................................................................................. 25
Figure 23 The regression model ........................................................................................................ 26
Figure 24 paired-t test ....................................................................................................................... 28

Table Content
Table 1 Response variable ................................................................................................................... 4
Table 2 Control variables .................................................................................................................... 5
Table 3 Constant variables .................................................................................................................. 5
Table 4 Noise variables ....................................................................................................................... 6
Table 5 Test matrix of experiment ....................................................................................................... 7
Table 6 Factor levels ........................................................................................................................... 8
Table 7 Experiment operations ............................................................................................................ 9
Table 8 Experiment result ................................................................................................................. 10
Table 10 Interactions analysis of three factor .................................................................................... 23

DOE Project Factor analysis for dissolution time of effervescent tablets

Abstract
It is generally accepted that the dissolution rate of effervescent tablets varies with own
properties as well as other environment factors. However, among various possible influential
factors, there are factors, such as volume of water, whose impact on dissolution rate is unclear.
In order to explore the impact of some factors, we design this experiment to gain observations.
Moreover, some factors, such as liquid temperature, are commonly known as a key factor. We
also include it in the experiment to examine its impact. The full-factorial designed experiment
identifies the temperature of water, volume of water, surface area of liquid and flavor of
effervescent tablet as effects. Two-factor interactions and three-factor interactions are involved.
Based on the collected data and result, we have some discussion, and summarize the
implication.
Key words: Dissolution Rate, Effervescent Tablet, Design of Experiment

Experiment Background & Objectives

Background
Effervescent tablets are popular among young people. It contains vitamins and has a pleasant
taste. If dropped into water, the tablet starts effervesce, goes up and down, and gradually
dissolves, and finally disappears. We observe that sometimes it takes only about one minute to
dissolute completely, while it may sometimes take several minutes. Therefore, we are curious
about what factors are having significant effects on the dissolution rate. Thanks to the
opportunity of DOE project, we are able to design a systematic experiment to probe into this
problem.

Objectives
The project aims at determining what the influential factors of effervescent tablets dissolution
rate are and their level of influence. Also, we are looking into the correlation between these
factors. Experimental design method is employed to study how response variable reacts to
controllable factors. We collect fairly reasonable amount of data, and then analyze them to find
out the influential factors of dissolution rate of effervescent tablets. Finally, we give our own
explanation on the result and implication presented.

DOE Project Factor analysis for dissolution time of effervescent tablets

Experiment Design
Initial Variable Analysis & Selection
The dissolution rate of the effervescent tablet under the same circumstance varies a lot because
of effervesce, which will release a huge amount of carbon dioxide and lead to the acceleration
of dissolution. Based on the observation of the dissolution of the effervescent tablet, we assume
that the influence of effervesce can be minimized carefully and will not affect the initial
intention of our experiment.
We believe that there may be several factors which will affect the rate of dissolution.
1.

Composition of the effervescent tablet

2.

Type of liquid

3.

Volume of water

4.

Temperature of water

5.

Surface area of liquid (related to the release of carbon dioxide)

6.

Surface area of the effervescent tablet

7.

Temperature and air pressure around

8.

Experiment method (whether stir is included)

9.

Place of experiment

10.

Time of ups and downs of the effervescent tablet

Variable Table
Response Variable
Table 1 Response variable

Response
Variable (units)
Dissolution Time
(s)

Normal
Operating
Level & Range

Measure
Precision

Recommended
Experiment
Settings

Relationship with the

Experiment Objective
Determine the

0 ~ 300 s

0.1 s

Stopwatch

dissolution rate of the

effervescent tablet

DOE Project Factor analysis for dissolution time of effervescent tablets

Control variable
Table 2 Control variables

Control

Normal

Variable

Operating

(units)

Level & Range

Measure

Recommended

Precision

Experiment Settings

Predicted Effects
Larger the volume

Volume of
water (ml)

0 ~ 500 ml

1 ml

of water is, larger

Measuring Pot

the rate of
dissolution will be.
Higher the

Temperature of
water ()

0 ~ 100

0.1

temperature of

Electronic

water is, larger the

Thermometer

rate of dissolution
will be.

Calculating by
Surface area of
2

liquid (cm )

0 ~ 200 cm2

1 cm2

measuring the volume

Larger the surface

of water with

area of liquid is,

measuring pot and the

larger the rate of

height of the container

dissolution will be.

with ruler
Flavor of the
effervescent

Orange/Peach

---

---

---

tablet

Constant variable
Table 3 Constant variables

Control

Normal

Measure

Recommended

Predicted Effects

Variable

Operating

Precision

Experiment

(units)

Level & Range

Type of liquid

---

---

Water

---

Composition of

---

---

Looking into

effervescent tablet

the effervescent

the list of

from the same brand

tablet

ingredients

will have the familiar

Settings

composition
Surface area of

---

---

Surface area of

Larger the surface

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DOE Project Factor analysis for dissolution time of effervescent tablets

the effervescent

the original

area of the

tablet

effervescent

effervescent tablet is,

tablet

larger the rate of

dissolution will be.

Experiment

---

---

No stir included

method

Stir will accelerate

the dissolution

Place of

---

---

Fixed place

---

experiment

Noise variable
Table 4 Noise variables

Control

Normal

Measure

Recommended Experiment

Predicted

Variable

Operating

Precision

Settings

Effects

(units)

Level & Range

Temperature

Fixed

Unnecessary

Shorten the experiment time

No effect

around

and do the experiment at the

same place to avoid the
change of temperature around

Air pressure

Fixed

Unnecessary

Ditto

No effect

Time of ups

0 ~ 3 times,

Unnecessary

---

No effect

and downs of

length of time

the effervescent

varies

around

tablet

Fishbone Diagram
Factors that could potentially affect the dissolution rate are summarized in the fishbone diagram
below. Based on this, the factors that are considered able to control given the experimental
conditions are selected in the following full factorial design.

DOE Project Factor analysis for dissolution time of effervescent tablets

Figure 1 Fishbone diagram of dissolution rate

Full factorial design

A four-factor two-level design is employed to reveal the main effects and the interaction effects
of four factors on dissolution time:
Tablet flavor (A)
Surface area of water (B)
Volume of water (C)
Temperature of water (D)

Test matrix
Table 5 Test matrix of experiment

Standard

Running

Flavor

Sequence Sequence

Surface

Volume

Temperature

area

of water

of water

11

-1

-1

-1

-1

-1

-1

-1

-1

32

27

-1

-1

17

-1

-1

-1

-1

19

-1

-1

-1

31

-1

12

-1

10

10

-1

-1

1
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DOE Project Factor analysis for dissolution time of effervescent tablets

13

11

-1

-1

22

12

-1

-1

20

13

-1

-1

18

14

-1

-1

-1

23

15

-1

-1

16

16

17

-1

-1

-1

15

18

-1

24

19

-1

30

20

-1

25

21

-1

-1

-1

22

-1

14

23

-1

24

-1

-1

-1

28

25

-1

21

26

-1

-1

-1

26

27

-1

-1

28

-1

-1

-1

29

-1

-1

29

30

-1

-1

31

-1

-1

32

-1

-1

-1

Factor levels
Table 6 Factor levels

-1

Flavor

Orange

peach

Surface area

small

large

Volume of water

150 ml

450 ml

Temperature of water

25 degrees

70 degrees

DOE Project Factor analysis for dissolution time of effervescent tablets

Conducting the experiment

Experiment operations
Table 7 Experiment operations

Date

2013/5/27

Experimenters

Girls in ZJ8# 612B and their friend

Time 18:00-21:00
Place

Dormitory

Equipment

500 ml measuring cup; digital thermometer (-50~300 degree); two

and materials

transparent cups (with small and large surface areas); effervescent

tablets (orange and peach flavors); hot and cold water

Operation
steps

1. Mixing the hot and cold water in the measuring cup and measure
the current temperature in the cup using the digital thermometer
2. Adding more hot water or cold water according to the degrees
shown on the thermometer
3. When the temperature of the water is appropriate, putting defined
amount of water into the transparent cup needed
4. Putting defined tablets into that cup and then start timing
immediately
5. Stop timing when the tablet completely dissolves

DOE Project Factor analysis for dissolution time of effervescent tablets

Snapshots of experiments

Figure 2 Snapshot of experiments

Analysis and result

Experiment data
Using Minitab, we design the order of each replication. And the experiment was conducted by
the operation order shown in Table 1. The time is the dissolution time of the tablets. More
explanation of the meaning of -1/1 is shown in table 2. We did 2 replications for each
experiment conditions, and the average time is shown in Figure 1.
Table 8 Experiment result

(s)

11

-1

-1

107

-1

-1

-1

-1

254.8
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DOE Project Factor analysis for dissolution time of effervescent tablets

-1

-1

249.1

32

93.2

27

-1

-1

115.7

17

-1

-1

-1

-1

240.5

19

-1

-1

-1

251.9

31

-1

100.7

12

-1

107.2

10

10

-1

-1

99.2

13

11

-1

-1

106.9

22

12

-1

-1

189.2

20

13

-1

-1

200.3

18

14

-1

-1

-1

223.8

23

15

-1

-1

243.9

16

16

108.4

17

-1

-1

-1

208.7

15

18

-1

103

24

19

-1

195.4

30

20

-1

108.8

25

21

-1

-1

-1

112.1

22

-1

201.7

14

23

-1

94.8

24

-1

-1

-1

113.1

28

25

-1

109.6

21

26

-1

-1

-1

207.2

26

27

-1

-1

95.9

28

-1

-1

-1

244

29

-1

-1

187.9

29

30

-1

-1

99.7

31

-1

-1

211.6

32

-1

-1

-1

213.1

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DOE Project Factor analysis for dissolution time of effervescent tablets

246.50

247.95

198.55

101.85

205.95

111.35

100.80

108.40

210.15

188.55

103.30

101.80

247.65

216.25

-1

112.60

97.55

-1
-1

-1

Figure 3 Result cubes

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DOE Project Factor analysis for dissolution time of effervescent tablets

Effects of factors
Significant factors

200

150

100
1

-1

-1

200

150

100
-1

-1

Figure 4 Main effect plot for the 4 factors

From the figure above, we can see that the surface area have little main effect on the dissolution
time, while the flavor, volume of water, temperature have significant main effects on the
dissolution time. And the temperature has the largest main effect.
For the flavor factor, the peach flavor tablets have shorter resolving time than the orange ones.
And if the volume of the water is large, the resolving time is shorter than that of the small
volume. As temperature rises, the dissolution time gets shorter.
If no interaction is detected between the surface area and other factors, this factor can be
negligible.

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DOE Project Factor analysis for dissolution time of effervescent tablets

-1

-1

-1
1

200

150
100

-1
1

200

150
100

-1
1

200

150
100

-1
1

200

150
100
-1

-1

Figure 5 Interaction plot for the 4 factors

From the figure above, we can find there is interaction between the flavor and temperature
factors. To test whether the main effects from each factor and the interaction are significant, we
check the normality plot.

Alpha =

.01)

99

AD

95
90

A
B
C
D

80

70
60
50
40
30

BCD

20

C
A

10
5

-50

-40

-30

-20

-10

10

Figure 6 The normality plot for effects

From Figure 6, we get the conclusion that the significant terms are flavor (A), volume(C),
temperature (D), two-factor interaction AD and three-factor interaction B(surface area)CD.
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DOE Project Factor analysis for dissolution time of effervescent tablets

To confirm the finding, we use ANOVA analysis to check the effects of the factors and the
interaction of the factors. And on a significance level of 99, we get the same result.

Figure 7 ANOVA table

We form a reduced model with only the significant terms, and get the following figures,
including the normality plot, half normal probability plot and Pareto Plot.

Alpha =

.01)

99

95
90

AD

80

70
60
50
40

BCD

A
B
C
D

30

20

10
5

-40

-30

-20

-10

Figure 8 Reduced Model Normality plot

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DOE Project Factor analysis for dissolution time of effervescent tablets

Alpha =

.01)

98

A
B
C
D

95

90

85

80

70
60

AD

50

40
30
20
10
0

BCD

10

20

30

40

Figure 9 Half normal probability plot

Pareto
Alpha =

.01)

2.79

A
B
C
D

D
A

AD
C
BCD
B
0

10

20

30

40

Figure 10 Pareto plot of the reduced model

And the ANOVA result from the reduced model is shown in Figure 9. The left factors and
interactions all have a p<=0.01. The result is quite satisfied.

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DOE Project Factor analysis for dissolution time of effervescent tablets

Figure 11 ANOVA for the reduced model

90

99

50

0
-4

10

-8

1
-10

-5

10

100

250

4.8

3.6

200

2.4

0
-4

1.2
0.0

150

-8
-8

-4

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Figure 12 Residual plot

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DOE Project Factor analysis for dissolution time of effervescent tablets

Effect of each factor

Flavor

175

170

165

160

155

150
-1

Figure 13 Main effect plot of flavor

The orange tablets take longer time to dissolve than the peach ones. We checked the content of
each type of the tablets, and found the types of pigment added in the tablets are not the same.
Maybe the dissolving ability of the pigment are not the same, thus causes the difference in the
dissolution time of the two flavors of tablets.

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DOE Project Factor analysis for dissolution time of effervescent tablets

Volume

170.0
167.5

165.0
162.5
160.0
157.5
155.0
-1

Figure 14 Main effect plot of volume

From the figure above, we draw conclusion that as the volume of water increases, the
dissolution time becomes shorter. From the research of others, we found little information of
the common relationship between the resolve speed and the volume of water, but from the study
of Shuhong Wang, Analysis on relationship between Cyclophosphamide dissolving speed and
amount of solvent, she found that if the amount of solvent is larger, the speed of dissolve is
higher.
And in our experiment, we found a phenomenon that when the tablets were dropped in larger
amount of water, the tablets would go up and down several times in the water, which gave the
tablets more opportunities to contact with the solvent, thus increase the dissolve speed.

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DOE Project Factor analysis for dissolution time of effervescent tablets

Temperature

220
200

180
160
140
120
100
-1

Figure 15 Main Effect Plot of temperature

It is clear that as the temperature rises, the dissolution time will be shorter. This result matches
our common sense well. And among the three factors, the temperature plays the most important
role in determination of the dissolution time.

2-factor-interacion
From the interaction plot of the flavor and temperature (the following figure), we detect the
lines are not parallel; there may be interaction between the two factors.

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DOE Project Factor analysis for dissolution time of effervescent tablets

240

-1
1

220

200
180
160
140
120
100
-1

Figure 16 Interaction plot for temperature and flavor

The contour plot (Figure 15) also confirms the interaction between these two factors. The
contour is curved, so the response is determined by the two factors together. And the response
surface (Figure 16) is a little bit twisted, leads to the same conclusion. The reason why these
two factors have interaction may be the feature of the pigment. We guess the pigment added in
the peach flavor have different dissolving ability against the pigment added in the orange flavor
at different level of temperature. But since the pigments are not the main components, so the
interaction between flavor and temperature is not so obvious.

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DOE Project Factor analysis for dissolution time of effervescent tablets

,
1.0
100
125
150
175
200
225

0.5

0.0

<

>

100
125
150
175
200
225
250
250

-0.5

-1.0
-1.0

-0.5

0.0

0.5

1.0

Figure 17 The contour plot for flavor and temperature

250
200

150
100

-1
0

1 -1

Figure 18 The response surface

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3-factor-interacion

102.550

101.325

199.350

222.525

105.075

109.875
1

231.950

226.950

-1

-1

-1

Figure 19 Cube plot of three factor interaction

From the cube plot (Figure 17) of the three-factor interaction, we can have a basic conception
of the data, but it is not so obvious that the three-factor terms BCD is significant in the effect of
the dissolution time. So we continue to do the interaction plot of B and CD, C and BD, D
and BC as figure 18, 19, 20.
Table 9 Interactions analysis of three factor

BC

Time

103.2

-1

227.2375

-1

106.2125

-1

-1

213.15

CD

Time

164.1375

-1

167.25

-1

166.2

-1

-1

152.2125

BD

Time

150.3375

-1

170.9125
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DOE Project Factor analysis for dissolution time of effervescent tablets

-1

162.5375

-1

-1

166.0125

time

-1

200

BC

BC
-1
1

150

100
D
-1
1

200
D

150

100
-1

Figure 20 The interactions between BC and D

time

-1

1
165

CD
-1
1

160
CD
155
150
B
-1
1

165
160
B
155
150
-1

Figure 21 The interactions between CD and B

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DOE Project Factor analysis for dissolution time of effervescent tablets

time

-1

1
170
165

BD
-1
1

160

BD

155
150
C
-1
1

170
165
160

155
150
-1

Figure 22 The interactions between BD and C

From the above figure, we can perceptional confirm that interactions between B and CD, C and
BD are significant at 5% confidence level. As a result, the three factor interaction is significant.
Howeverit may require a reasonable explanation of the three factor interaction as the main
effect of the surface area is not significant and the high order interaction is not so much familiar
in the normal experiment. We went back to check the data and find that the response factor is
largely influenced by the factor D (water temperature). And the cross-sectional area of the
experimental cup, namely the factor B surface area, and the water volume has relationship
physically. As we all know,
V = S h = 2 h
S = C h + 2S = 2rh + 2 2
Then we guess this may contribute some hidden effects of three factor interaction.
The room temperature is about25 . The material of the cup is plastic. According to the
previous study of the scientists, water temperature decreases faster with higher differences with
the outer temperature, and the total surface area of the water body experimented may have
larger effect on the cooling process. Checking the interaction plot of BC and D, the difference
of the two lines slopes are not so big, while the interaction between BD and C, CD and B are
much significant.
It is sure that the dissolution time is shorter with high water temperature, the interaction plot
also shows that the response factor also has difference performances under the condition of
different total surface area (BC), and this kind of difference is more obvious when temperature
is higher. So when the water temperature is high, the hidden effect of BC becomes significant.
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DOE Project Factor analysis for dissolution time of effervescent tablets

And this kind of interactions cannot be rejected in our data, we try to do normality of the
response time, the BCD is always in the accept family with near the boundary value (p=0.05).
This may be kind of Marginal utility.

Regression model

Figure 23 The regression model

The final model is:

= 162 - 10.2 + 2.72 - 6.01 - 57.7 + 7.65 *
- 4.28 **
Although there are two outliers, we find R-Sq is quite large, and there are only 32 observations,
so we do not eliminate the outliers.

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DOE Project Factor analysis for dissolution time of effervescent tablets

Conclusion and discussion

The following conclusions can be drawn from this study:
a. The main effects of flavor, volume of water and temperature of water are significant.
b. The two-factor interactions between flavor and temperature is also significant.
c. Surface area does not show any significant effects at either main effect or two-factor
interactions.
d. The three-factor interaction of flavor, volume of water and temperature of water is
significant.
e. = 162 - 10.2 + 2.72 - 6.01 - 57.7 + 7.65 *4.28 **

Model validation
From the above test, we form a model of the factors and interactions:
Time = 162 10.2 + 2.72 6.01 57.7 + 7.65
4.28 .
To evaluate the model, we conduct 8 more runs to compare the anticipated time and the real
time. The settings of the level of the factors are shown below with the anticipated value and
experiment value:
Table 10 Evaluation of the model

-1

99.28

103.0

-1

202.84

206.0

-1

-1

119.86

112.4

-1

114.76

104.8

-1

-1

-1

242

246.3

-1

-1

238.54

229.9

94.18

90.1

-1

-1

206.3

208.2

Using a 95 significant level paired-t test, we check whether the anticipated value matches the
actual time. From the result, we find the difference of the two sets of data will fall into the
interval (-2.92, 7.19). And we cannot reject the hypothesis that the anticipate value and actual
value are equal.
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DOE Project Factor analysis for dissolution time of effervescent tablets

Figure 24 paired-t test

28