AEGAEUM JOURNAL ISSN NO: 0776-3808

FORMULATION AND EVALUATION OF SUBLINGUAL TABLET OF ENALAPRIL

MALEATE BY 32 FULL FACTORIAL DESIGN

Satyajit Sahoo1*, Ankit Patel1, Santosh Kumar Vaidya2, Dharmesh K. Golwala2

& Prasanta Kumar Mohapatra3

1
C.U. Shah College of Pharmacy and Research, Wadhwan , Surendranagar, Gujarat, India.
2
Shankersinh Vaghela Bapu Institute of Pharmacy, Vasan, Gandhinagar, Gujarat, India.
3
Moradabad Educational Trust Group of Institutions, Faculty of Pharmacy, Uttar Pradesh, India.

*Corresponding Author:
Dr Satyajit Sahoo,

Associate Professor,
C.U. Shah College of Pharmacy and Research, Gujarat, India

E mail: satyajitccpr@gmail.com

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 894

AEGAEUM JOURNAL ISSN NO: 0776-3808

ABSTRACT :
The aim of this work was to formulate and evaluate sublingual tablets of Enalapril maleate for
rapid management of Hypertension. In the present work, the metallic taste of Enalapril maleate
was masked by using Kyron T-114 in 1:2 ratio. The Drug-Resin Complex was formulated as
sublingual tablets using Cross Povidone (X1) and Avicel PH102 (X2) by direct compression
method. The sublingual tablets were evaluated such as thickness, hardness, % Friability, Wetting
time, disintegration time, Water absorption ratio and % CDR. In this study, the fast release of
tablets depends on the concentration of Cross Povidone (X1) and Avicel PH102 (X2). The
selected formulation showed the fastest release of the tablets in 45 s. Stability study was
performed by taking an optimized formulation and it was observed stable. The sublingual tablets
showed acceptable results in all studies. The results indicate that the formulation can be used for
rapid management of Hypertension. Also, Enalapril maleate’s bioavailability may be increased
by selecting sublingual route of administration.
Key words: Sublingual tablets, Hypertension, Enalapril Maleate, Cross Povidone, Avicel PH
102, Kyron T- 114, 32 full factorial designs

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 895

AEGAEUM JOURNAL ISSN NO: 0776-3808

INTRODUCTION:

Development of a formulation involves a great deal of study and experimental work to get
optimum results. First pass metabolism can be overcome by sublingual drug delivery, and quick
drug delivery into the systemic circulation can be obtained. Sublingual administration can offer
an attractive alternative route of administration. The advantage of the sublingual drug delivery is
that the drug can be directly absorbed into systemic circulation bypassing enzyme degradation in
the gut and liver. These formulations are particularly beneficial to pediatric and geriatric patients.
In addition sublingual mucosa and abundance of blood supply at the sublingual region allow
excellent drug penetration to achieve high plasma drug concentration with rapid onset of an
action [1]. Oral mucosal drug delivery is an alternative method of systemic drug delivery that
offers several advantages over both injectable and enteral methods. Because the oral mucosa is
highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic
circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver [2].
Sublingual means literally ‘under the tongue’ refers to a method of administering substances via
the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the
tongue rather than via the digestive tract [3]. Medically, sublingual drug administration is applied
in the field of cardiovascular drugs, steroids, some barbiturates and enzymes. It has been a
developing field in the administration of many vitamins and minerals which are found to be
readily and thoroughly absorbed by this method [4]. The absorption of the drug follows in this
way: Sublingual > Buccal > Gingival > Palatal. Due to high permeability and rich blood supply,
the sublingual route can produce rapid onset of action [5]. Factors affecting the sublingual
absorption are Lipophilicity of drug, Solubility in salivary secretion, pH and pKa of the saliva,
binding to oral mucosa, Thickness of oral epithelium and Oil-to-water partition coefficient [6-9].

Direct compression does not require the use of water or heat during the formulation procedure
and is the ideal method for moisture and heat- labile medications [10]. Hypertension is a common
cardiovascular disorder, which is an important risk factor for coronary artery diseases.
Hypertension (HTN) is the term used to denote elevated blood pressure (BP). It is defined as the
condition in which BP remains consistent to systolic blood pressure (SBP) >140 mmHg and
diastolic blood pressure (DBP) >90 mmHg [11]. Hypertension as worldwide recognized public
health problem is one of the leading causes of death influenced by cardiovascular diseases
(CVD) like heart failure (HF), coronary heart disease (CHD), myocardial infarction (MI) and
stroke. According to World Health Organization (WHO) and International Society of
Hypertension (ISH) from 2003 it is estimated that hypertension cause 4.5% of global disease
burden and is a prevalent in many developing countries as in the developed world [12]. Under a
threshold of 140/90 mmHg, the World Health Organization estimates that nearly 1 billion people
in developed and developing countries are affected with hypertension. About 1 in 8 deaths
worldwide is due to hypertension and 4 million people die annually thus making it the third
largest killer in the world [13].

MATERIALS AND METHODS

Enalapril Maleate was obtained from West Coast Pharmaceuticals, India. Sodium starch
glycolate was obtained from Chemdyes Chemicals, India. Crospovidone and Cross Carmellose
Sodium were obtained from Seva fine Chemicals, India. Kyron T114 was obtained from Corel

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 896

AEGAEUM JOURNAL ISSN NO: 0776-3808

Pharma Chem, India. Avicel PH102 was obtained from Chemdyes Chemicals, India. All the
polymers received were of pharmaceutical grade. Other materials used were of analytical grade.

Drug Excipients Compatibility Study

Drug-Excipients interaction plays a vital role in achieving stability of drug in dosage form.
Fourier transform infrared spectroscopy (FT-IR) was used to study the physical and chemical
interactions between drug and excipients. FT-IR spectra of Enalapril Maleate, Crospovidone and
Avicel PH102 and their mixture were recorded using KBr mixing method on FT-IR instrument.
(FTIR-1700, Shimadzu, Kyoto, Japan) [14].

Preparation of Drug-Kyron T-114 complex

200 mg of activated resin was placed in a beaker containing deionised water and allow to swell
for 30 min. Accurately weighed Enalapril Maleate 100 mg was added and stirred for one hour.
The mixtures were filtered and residue was washed with deionised water. DRC was then washed
with sufficient quantity of deionised water for three times to remove loosely adsorbed drug from
resinate surface. DRC was allowed to dry at room temperature and was stored in tightly closed
container and used in further studies [15].
The above procedure was followed to prepare DRC in different ratios like 1:1, 1:1.5, 1:2, 1:2.5
and 1:3.

Determination of Drug Loading in DRC:

After drying of DRC, 30 mg of DRC was taken and dissolved in to 50 ml of 0.1N HCL in a
volumetric flask. The solution was sonicated in to sonicator for 30 min. After sonication the
solution was put to settle down the solid particles at the bottom of the flask. 1 ml of supernatant
liquid was taken and diluted up to 10 ml with 0.1N HCl. Lastly, the absorbance was taken into
the U.V. Spectrophotometer at λ max 210.5 nm.

Table 1 : Percentage Drug loading was found in DRC

Ratio of Drug and Resin Percentage Drug Loading
1:1 18.8%
1:1.5 33.86%
1:2 44.4%
1:2.5 28.8%
1:3 28%
It was observed that maximum drug loading in DRC was found in 1:2 ratio of Drug and Resin.

Preparation of sublingual tablets

Drug Resin complex was prepared by using Kyron T114 as a resin. Remaining ingredients was
weighed except Talc. All the ingredients were passed through 40# sieve. The Powder blend was
mixed thoroughly in a polythene bag. Finally the blend was lubricated with Talc. The blend was
compressed using rotary tablet compression machine using 7 mm punch set [16].
The aim was to formulate, develop and optimize sublingual tablet of Enalapril Maleate
containing various polymers. For the selection of particular polymer various preliminary trial
batches were carried out with Crosspovidone, Sodium starch glycolate and Crosscarmellose

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 897

AEGAEUM JOURNAL ISSN NO: 0776-3808

sodium. Different concentrations of polymer were used to prepare sublingual tablets as shown in
Table 2. The prepared formulations were evaluated.

Table 2: Preparation of trial batches

Ingredients T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12
DRC 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5
Pearlitol SD
25 25 25 25 25 25 25 25 25 25 25 25
200
Avicel PH102 15 20 25 30 15 20 25 30 15 20 25 30
Lactose DCL 31 25 19 13 31 25 19 13 31 25 19 13
Cross - - -
2 3 4 5 - - - - -
povidone
Sodium Starch - - -
- - - - 2 3 4 5 -
Glycolate
Cross
Carmelose - - - - - - - - 2 3 4 5
Sodium
Citric acid 1 1 1 1 1 1 1 1 1 1 1 1
Aspartame 2 2 2 2 2 2 2 2 2 2 2 2
Talc 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Total Weight
100 100 100 100 100 100 100 100 100 100 100 100
(mg)

Based on results obtained in trial batches the Factors and level of factors were decided. It was
observed that Cross Povidone alone was not able to produce fast disintegration. So, it was
combined with Avicel PH102 polymer to increase the fast disintegration of the prepared tablets.
The main characteristic of sublingual tablet is to dissolve quickly. In order to dissolve quickly
rapid disintegration of tablet is required. So, concentration of super disintegrating agent plays a
crucial role in formulation of tablets. Hence, the two factors for Factorial design were:
i) Concentration of Cross Povidone (X1)
ii) Concentration of Avicel PH102 (X2)
Two levels for each factor were selected to study the effect of X1 and X2.

Experimental Design of sublingual tablets of Enalapril maleate containing Cross Povidone

and Avicel PH102

To achieve the formulation with desired strength, quick disintegration and drug release, the
formulation prepared by using different combination of Cross Povidone and Avicel PH102
were optimized and evaluated using 32- full factorial design.

Full factorial design

This design is useful when a detailed analysis of higher order interactions among the factors is
needed. Runs are made at all possible combinations of factor levels. As the number of runs
required increases rapidly as the number of factors increases, full factorials are usually used
when a relatively small set of factors that are known to be important are available or when
collecting a large number of observations is feasible. More information is obtained with less
work and effects are measured with maximum precision.
The number of experiments required for these studies is dependent on the number of independent
variables selected. The response (Y) is measured for each trial.

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 898

AEGAEUM JOURNAL ISSN NO: 0776-3808

Y = β0 + β1 X1 + β2 X2 + β12 X1 X2 + β11X12 + β22 X22

In The 32- full factorial design 2 independent factors were evaluated, each at 3 levels, and
experimental trials were performed for all 9 possible combinations. The design layout of 32- full
factorial design as shown in table 3 and table 4.

Two independent variables were selected as below:

X1 = % w/v concentration of Cross Povidone
X2 = % w/v concentration of Avicel PH102

Table 3: Variables for experimental design

Variables for 32- full factorial design
Independent variables Dependent variables
X1 X2 Y1 Y2 Y3
Concentration of Concentration of Hardness Disintegration % CDR
Cross Povidone Avicel PH102 time

Table 4: Three levels of each variable

Level X1 (% w/v) X2 (% w/v)
Low (-1) 3 18
Medium (0) 4 23
High (+1) 5 28

Table 5: Formulation of Factorial Batches

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9
DRC 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5 22.5
Pearlitol SD
25 25 25 25 25 25 25 25 25
200
Avicel PH102 18 23 28 18 23 28 18 23 28
Lactose DCL 27 21 15 27 21 15 27 21 15
Cross
3 4 5 3 4 5 3 4 5
povidone
Citric acid 1 1 1 1 1 1 1 1 1
Aspartame 2 2 2 2 2 2 2 2 2
Talc 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Total Weight
100 100 100 100 100 100 100 100 100
(mg)

Drug Excipients Compatibility Study

Fourier transform infrared spectroscopy (FT-IR) was used to study the physical and chemical
interactions between drug and excipients. FT-IR spectra of Enalapril Maleate, Kyron T-114,
Cross Povidone, Avicel PH102 and their mixture of Enalapril Maleate, Kyron T-114, Cross
Povidone, Avicel PH102 were recorded by using KBr mixing method on FT-IR instrument. The
drug exhibited peaks due to Carboxylic group, C-N, Aromatic ring, -C-O and C=O stretching. It
was observed that there were no or very minor changes in drug main peaks in the IR spectra of
the mixture and pure drug. The FTIR study revealed no physical or chemical interaction of
Enalapril Maleate, Kyron T-114, Cross Povidone, Avicel PH102 [17].

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 899

AEGAEUM JOURNAL ISSN NO: 0776-3808

Figure 1.1 FT-IR spectra of Enalapril Maleate Figure 1.2 FT-IR spectra of Drug and Resin
(Enalapril Maleate and Kyron T114 )

Figure 1.3 FT-IR spectra of Drug Resin Complex , Crosspovidone and Avicel PH102

EVALUATION PARAMETER:

Thickness
The average thickness of all the formulations was between 2.6 to 3.1 mm [18].

Weight variation
The average weight of tablet formulations was within the range of 97.3±2.08 to 101±4.35 mg.
So, all tablets passed weight variation test as the % weight variation was within the
pharmacopoeial limits of 10% of the weight [19].

Hardness
The measured hardness of tablets of each batch ranged between 2.2±0.15 to 3.1±0.17 kg/cm2.
This ensure good handling characteristics of all batches.[20].

% Friability
The % friability of all the batches was between 0.40 to 0.81 % which was less than 1%. So %
friability was within the limit [21].

Disintegration time
The disintegration time of all the batches was between 45 to 52 sec. It was observed that as the
concentration of Cross Povidone increases, then disintegration time decreases. On the other
hand, as the concentration of Avicel PH102 increases, then disintegration time increases [22].

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 900

AEGAEUM JOURNAL ISSN NO: 0776-3808

Wetting time
The wetting time of all the batches was found to be between 43 to 52 sec [23].

Drug content
The percentage drug content of the all batches was between 96.93% to 99.12%, which is within
acceptable limits indicate dose uniformity in each batch [24].

In-vitro dissolution study

From dissolution study it was concluded that as concentration of Cross povidone increases
amount of drug released decreases and as the concentration of Avicel PH102 increases amount of
drug released increases [25].

Table 6: In-vitro Dissolution of Batch F1-F9

Time % Drug Release
(in min) F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
3 18.36 20.11 23.76 25.56 30.96 28.80 24.12 27.72 29.88
6 38.98 41.51 46.57 50.18 54.17 52.36 49.09 52.71 53.81
9 59.36 61.54 65.91 70.98 74.27 72.09 68.09 75.33 77.86
12 76.97 79.52 83.55 87.57 93.04 90.85 85.02 89.78 91.25
15 85.31 88.96 91.93 93.45 97.15 95.67 92.69 94.96 96.80

Figure 2: Drug release profile of batch F1-F9

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 901

AEGAEUM JOURNAL ISSN NO: 0776-3808

Statistical Analysis

The statistical analysis of the factorial design batches was performed by multiple linear
regression analysis. The hardness (Y1), disintegration time (Y2) and % drug release after 25 min
of Enalapril maleate (Y3) were selected as dependent variables. Table 7 shows list of variables.

The polynomial equation for 32 factorial designs is described as follows:

Y = β0 + β1X1 + β2X2+ β12 X1 X2+ β11X12 + β22X22 …………………………………..(1)

where Y is dependent variable, β0 arithmetic mean response of nine batches, and β1 estimated
coefficient for factor X1. The main effects (X1 and X2) representthe average result of changing
one factor at a time from its low to high value. The interaction term “X1X2” shows how the
response changes when the two factors change simultaneously. The polynomial terms (X12and
X22) are included to investigate nonlinearity [26,27].

Table 7: Experimental runs and measured responses

X2 Y2 Y3
X1 Y1
(conc. of Disintegr % Cumulative
Batch (conc. of Cross Hardness
Avicel ation Drug release
Povidone) (kg/cm2)
PH102) time (sec) after 15 min.

F1 -1 -1 2.2±0.15 52±1 85.31

F2 0 -1 2.4±0.15 49.3±1.52 88.96

F3 +1 -1 2.7±0.10 50.6±2.08 91.93

F4 -1 0 2.5±0.22 48.3±2.08 93.45

F5 0 0 2.8±0.10 45±2 97.15

F6 +1 0 3.1±0.17 48±2 95.67

F7 -1 +1 2.5±0.25 50.3±1.52 92.69

F8 0 +1 2.9±0.17 48.3±1.52 94.96

F9 +1 +1 3.2±0.30 49.6±2.51 96.80

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 902

AEGAEUM JOURNAL ISSN NO: 0776-3808

The fitted equations (full model) relating the responses that is, hardness (Y1), disintegration time
(Y2) and % cumulative drug release after 15 min of Enalapril maleate (Y3) to the transformed
factor are shown in Table 7. The polynomial equations can be used to draw conclusions after
considering the magnitude of coefficient and the mathematical sign it carries (i.e. positive or
negative). Data were analyzed using Design of Expert version 9.

R2 values for hardness (Y1), disintegration time (Y2) and % drug release after 15 min of Enalapril
maleate (Y3) were 0.9962, 0.9681 and 0.9525 respectively indicating good correlation between
dependent and independent variables. There was no need to develop reduced models because
response variable were significant i.e. P < 0.05. The terms with P < 0.05 were considered
statistically significance and retained in the full model.

The results of ANOVA suggested that F values calculated for hardness (Y1), disintegration time
(Y2) and % drug release after 15 min. of Enalapril maleate (Y3) were 157.80, 18.24 and12.03
respectively (Table 9).Calculated F values were greater than tabulated for all dependent variables
therefore factors selected have shown significant effects. From the results of multiple regression
analysis, it was found that both factors had statistically significant influence on all dependent
variables as p <0.05 (Table 8).

Table 8: Summary of Results of Regression Analysis

Hardness (kg/cm2)
Response
β0 β1 β2 β12 β11 Β22 R2 value
(Y1)
Coefficient +2.80 +0.30 +0.22 +0.050 +2.94 -0.15
0.9962
P Value 0.0008 0.0002 0.0005 0.0577 1.000 0.0079
Disintegration time (sec)
Response
β0 β1 β2 β12 β11 Β22 R2 value
(Y2)
Coefficient +45.59 -0.40 -0.62 +0.18 +2.27 +2.92
0.9681
P Value 0.0188 0.1896 0.0800 0.5887 0.0117 0.0057
Cumulative Drug release after 15 min. (%) of Enalapril maleate
Response
β0 β1 β2 β12 β11 Β22 R2 value
(Y3)
Coefficient +96.12 +2.16 +3.04 -0.63 -1.05 -3.65
0.9525
P Value 0.0337 0.0311 0.0124 0.4289 0.3602 0.0331

Table 9: Results of the ANOVA for dependent variables

Source of
DF SS MS F P
Variation
Hardness (kg/cm2)
Regression 5 0.88 0.18
Residual 3 3.33 1.11 157.80 0.0008
Total 8 4.21 1.29

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 903

AEGAEUM JOURNAL ISSN NO: 0776-3808

Disintegration time (sec)

Regression 5 30.65 6.13
Residual 3 1.01 0.34 18.24 0.0188
Total 8 31.66 6.44
Cumulative Drug release after 15 min. (%) of Enalapril maleate
Regression 5 113.85 22.77
Residual 3 5.68 1.89 12.03 0.0337
Total 8 119.53 24.66

Full and reduced model for Hardness

The contour plot and response surface plot for Hardness was observed in Fig. 3.1 and Fig. 3.2
respectively and revealed that a corresponding increase of Hardness was observed with increase
in concentration of Avicel PH 102. Moreover, the results also indicated that the effect of Avicel
PH 102 was more significant. From regression it is observed that X1 and X2 was significant
model term which affect the particle Hardness. Interaction and nonlinearity was not observed.
For Hardness, the significant levels of the coefficients β12 and β22 were found to have P value
of 0.577 and 1.000. So, it was omitted from the full model to generate a reduced model. The
coefficients β0, β1, β2 and β11 were found to be significant at P < 0.05. Hence, they were
retained in the reduced model.
The reduced model for Hardness was:
Hardness = + 2.8 +0.3* X1 + 0.22*X2 –0.15 X22

Design-Expert® Software Hardness Design-Expert® Software

1.00
Hardness Hardness
Design Points Design points above predicted value
3.2 Design points below predicted value
3.2
2.2 0.50
3.3
2.2
3.04597
X1 = A: conc. of Cross Povidone 3
B: conc. of Avicel PH102

X1 = A: conc. of Cross Povidone

X2 = B: conc. of Avicel PH102 X2 = B: conc. of Avicel PH102
Hardness

2.87344 2.7
0.00

2.70092 2.4

2.52839 2.1
-0.50

2.35586 1.00 1.00

0.50 0.50
-1.00 0.00 0.00
-1.00 -0.50 0.00 0.50 1.00 -0.50 -0.50
B: conc. of Avicel PH102 A: conc. of Cross Povidone
-1.00 -1.00

A: conc. of Cross Povidone

Fig 3.1 : Contour plot showing the effect of Cross Fig 3.2 : Response surface plot showing the effect of
Povidone (X1) and Avicel PH 102 (X2) on Hardness Cross Povidone (X1) and Avicel PH 102 (X2) on
(Y1) Hardness (Y1)

Full and reduced model for Disintegration time of Enalapril Maleate

The contour plot and response surface plot for Disintegration time was observed in Fig. 4.1 and
Fig. 4.2 respectively and revealed that a corresponding decrease in the disintegration time of
tablet was observed with increase in concentrations of Crosspovidone. Moreover, the regression
coefficient values of both factors can be concluded that the disintegration time appeared to
decrease more with an increasing amount of the Crosspovidone and decreasing the amount of
Avicel PH 102. Interaction and nonlinearity was not observed.
For disintegration time, the significant levels of the coefficients β1, β2 andβ12 were found to
have P value of 0.1896, 0.0800 and 0.5887. So, it was omitted from the full model to generate a

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 904

AEGAEUM JOURNAL ISSN NO: 0776-3808

reduced model. The coefficients β0, β11 and β22 were found to be significant at P < 0.05.
Hence, they were retained in the reduced model.
The reduced model for Disintegration time was:
Disintegration time = +45.58 +2.26* X1 X2 + 2.91* X22

Design-Expert® Software
Design-Expert® Software Disintegration Time
1.00
48.7522
Disintegration Time
Disintegration Time Design points above predicted value
48.7522
Design Points Design points below predicted value
52 52
52
45 45
0.50

X1 = A: conc. of Cross Povidone

Disintegration Time
50.25
X2 = B: conc. of Avicel PH102
B: conc. of Avicel PH102

X1 = A: conc. of Cross Povidone

X2 = B: conc. of Avicel PH102 47.6816 48.5

0.00
46.75

45

46.611
-0.50
1.00 1.00
0.50 0.50
0.00 0.00
49.8227
-0.50 -0.50
50.8933 48.7522 49.8227 B: conc. of Avicel PH102 A: conc. of Cross Povidone
-1.00 -1.00 -1.00

-1.00 -0.50 0.00 0.50 1.00

A: conc. of Cross Povidone

Fig 4.2 : Contour plot showing the effect of Cross

Fig 4.1 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on
Povidone (X1) and Avicel PH 102 (X2) on Disintegration
Disintegration time (Y2)
time (Y2)

Full and reduced model for % CDR at 15 min.

The contour plot and response surface plot for % CDR at 15 min. was observed in Fig. 5.1 and
Fig. 5.2 respectively and revealed that a corresponding decrease in the % drug release of tablet
was observed with increase in concentrations of Avicel PH 102 and decrease in concentration of
Crosspovidone. Interaction and nonlinearity was not observed.

For disintegration time, the significant levels of the coefficients β12 and β11 were found to
have P value of 0.4289 and 0.3602. So, it was omitted from the full model to generate a reduced
model. The coefficients β0, β1, β2 and β22 were found to be significant at P < 0.05. Hence,
they were retained in the reduced model.
The reduced model for % CDR was:
% CDR = +96.12 + 2.15*X1 + 3.04*X2 – 3.64*X22

Design-Expert® Software %CDR Design-Expert® Software

1.00
%CDR 93.6235
%CDR
Design Points Design points above predicted value
97.15 Design points below predicted value
97.15
85.31 0.50 98
85.31
B: conc. of Avicel PH102

X1 = A: conc. of Cross Povidone X1 = A: conc. of Cross Povidone 94.75

X2 = B: conc. of Avicel PH102 X2 = B: conc. of Avicel PH102
95.6299
0.00 91.5
%CDR

88.25
93.6235
-0.50
85

91.6172
89.6108
87.6044 1.00 1.00

-1.00 0.50 0.50

-1.00 -0.50 0.00 0.50 1.00 0.00 0.00

-0.50 -0.50
B: conc. of Avicel PH102 A: conc. of Cross Povidone
-1.00 -1.00
A: conc. of Cross Povidone

Fig 5.1 : Contour plot showing the effect of Cross Fig 5.2 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on % CDR Povidone (X1) and Avicel PH 102 (X2) on %CDR (Y3)
(Y3)

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 905

AEGAEUM JOURNAL ISSN NO: 0776-3808

Validation by Check point batch

To confirm the validity of response surface plot and equation generated by multiple regression
analysis, a check point batch was prepared shown in table 10. An overlay plot was obtained by
adding desired range of evaluation parameters from Design Expert 9. The overlay plot is shown
in Fig. 6. Yellow colour area in overlay plot showed optimum concentration range for desired
result. A batch was prepared by taking concentration of Cross Povidone (X1) and concentration
of Avicel PH 102 (X2) observed in overlay plot and the actual responses were evaluated from the
prepared check point batch.The overlay plot indicated that optimum concentration which showed
the best result. The practically obtained values were closer to the predicted values as shown in
table 11. Thus, it justified the validation of design.
Design-Expert® Software
1.00
Overlay Plot
Overlay Plot

Hardness
Disintegration Time
%CDR 0.50
Design Points
B: conc. of Avicel PH102

%CDR: 96 Hardness: 3
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
0.00

Hardness: 2.73885
Disintegration 47.3922
%CDR: 93.8173
X1 0.49
-0.50 X2 -0.62
Hardness: 2.5 Disintegration Time: 47

Disintegration Time: 50
%CDR: 88
Disintegration Time: 50
-1.00

-1.00 -0.50 0.00 0.50 1.00

A: conc. of Cross Povidone

Fig 6: Overlay plot of Check point batch

Table 10: Formulation of Check Point Batch

Batch Code Coded Value Actual Value
CP1 X1 X2 X1 (mg) X2 (mg)
+0.5 -0.62 4.5 19.5

Table 11: Results of Check point batch method

Response Predicted value Experimental value
Hardness (kg/cm2) 2.738 2.928
Disintegration time (sec) 47.392 48.932
% CDR at 20 min. of Enalapril
93.817 95.968
maleate

Accelerated stability study

The stability study indicated that the optimized formula was physically and chemically stable
with no significant changes in any of the evaluated parameters when stored at the 40oC and at
75% ± 5 RH conditions. From stability studies it was concluded that the sublingual tablets of
Enalapril maleate was stable [28].

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 906

AEGAEUM JOURNAL ISSN NO: 0776-3808

Table 12: Result of short term stability study of optimized batch

Evaluation Parameters Before Stability period After Stability period
Hardness (kg/cm2) 2.8±0.10 2.7±0.60
Disintegration time(sec) 45±2 44±2
% CDR at 20 min 97.15 96.52

RESULT: Generally for sublingual drug delivery fast dissolving tablets are available. Problem
associated with sublingual tablet formulations is that there is always a risk that the patients will
swallow part of the dose before the active substance has been released and absorbed locally into
the systemic circulation. This could result an unwanted prolongation of the pharmacological
effect. Preliminary screening was performed to mask the metallic taste of Enalapril maleate by
using resin Kyron T-114. Also, for selection of polymers (superdisintegrants) and its
concentration by using different superdisintegrants like Cross Povidone, Sodium Starch
Glycolate and Cross Carmelose Sodium. It was observed that Cross Povidone shows the best
results among the three superdisintegrants. Preformulation studies were carried out in order to
establish the compatibility between the drug resin complex and polymers by infrared
spectroscopy. The studies revealed that, drug resin complex and polymers were satisfactorily
compatible. The sublingual tablets were prepared by using 32 full factorial design by employing
Cross Povidone and Avicel PH102 to decrease disintegration time. From the results obtained
from the preliminary screening, two factors were selected i.e. concentration of Cross Povidone
(X1) and concentration of Avicel PH 102 (X2) as independent variables. Dependent variables
selected were Hardness (Kg/cm2), Disintegration time (sec) and % CDR. The prepared
formulations were evaluated for different parameters like Hardness, Disintegration time, weight
variation, thickness, friability, content uniformity, water absorption ratio and drug release
studies.

DISCUSSION: On the basis of Desirability approach, formulation containing Cross Povidone

and Avicel PH102 in concentration of 4.0% w/v and 23 % w/v batch was selected as an
optimized batch. From the in vitro study, it was found that the developed formulation was
provided fast release of the drug at 15 min. by formulating in the form of sublingual Enalapril
maleate tablets.

CONCLUSION
Sublingual tablets of Enalapril maleate were prepared by direct compression method. Firstly, the
metallic taste of Enalapril maleate was masked by using Kyron T-114 in 1:2 ratio . Later on this
Drug-Resin Complex was formulated as sublingual tablets using Cross Povidone (X1) and
Avicel PH102 (X2). In direct compression method tablets parameters such as hardness,
disintegration time and % CDR were found to be acceptable. Selected batch showed Hardness
2.8±0.10 , disintegration time 45 sec and percentage cumulative drug release was found 97.15 in
15 minutes. The 32 factorial design was used to select optimized batch. Sublingual tablets
showed no significant changes in percentage cumulative drug release after storage of two weeks.
Faster dissolution of drug could be achieved which indicates faster onset of action. Thus the

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 907

AEGAEUM JOURNAL ISSN NO: 0776-3808

system was suitable for obtaining rapid dissolution of dosage form in sublingual drug delivery
system.

ACKNOWLEDGEMENT
The authors are thankful to West Coast Pharmaceuticals, India for supplying a gift sample of
Enalapril maleate. Sodium starch glycolate and Avicel PH102 were obtained from Chemdyes
Chemicals, India. Crospovidone and Cross Carmellose Sodium were obtained from Seva fine
Chemicals, India. Kyron T114 was obtained from Corel Pharma Chem, India.

CONFLICTS OF INTEREST: There is no conflict of interest for all authors.

REFERENCES

1. Tas C, Bayrak Z and Tasdemir U, “Formulation of Zolmitriptan sublingual tablets

prepared by direct compression with different polymer: In vitro and in vivo evaluation”,
European Journal of Pharmaceutics and Biopharmaceutics, vol. 78, no. 3, (2011), pp.
499-505.
2. Aghera Nikunj, Shah Suresh and Vadalia Kantilal, “Formulation and evaluation of
sublingual tablets of Losartan potassium”, Asian Pacific Journal of Tropical Disease,
vol. 2, (2012), pp. S130-S135.
3. M.D. Nehal Siddiqui, Garima Garg and Pramod Kumar Sharma, “A Short Review on A
Novel Approach in Oral Fast Dissolving Drug Delivery System and Their Patents”,
Advances in Biological Research, vol. 5, no. 6, (2011), pp. 291-303.
4. Kumari Sunita, Visht Sharad, Sharma Pramod Kumar and Kumar Rakesh, “Fast
dissolving Drug delivery system: Review Article”, Journal of Pharmacy Research, vol. 3,
no. 6, (2010), pp. 1444-1449.
5. Patel KN, Pancholi SS, “Sublingual route for systemic drug delivery:A Pharmaceutical
Review”, International Journal of Research in Pharmaceutical and biomedical Sciences,
vol. 3, no. 2, (2012), pp. 913-923.
6. Saha Puja, Verma Sushma and Das Pratik Swarup, “Sublingual Drug Delivery: An
Indication of Potential Alternative Route”, Int J Curr Pharm Res, vol. 9, no. 6, (2017),
pp. 5-7.
7. Narang Neha and Sharma Jyoti, “Sublingual Mucosa as A Route For Systemic Drug
Delivery”, International Journal of Pharmacy and Pharmaceutical Sciences, vol. 3, no.
2, (2011), pp. 18-22.
8. Patel Priyank, Makwana Sandip, Jobanputra Urvish, Ravat Mihir, Ajmera Ankit and
Patel Mandev, “Sublingual route for the systemic delivery of Ondansetron”, Int. J. Drug
Dev. and Research, vol. 3, no. 4, (2011), pp. 36-44.
9. Sarkhejiya Naimish, Patel Vipul and Pandya Devang, “Sublingual Delivery: A Promising
Approach To Improve Bioavailability”, An International Journal of Pharmaceutical
Sciences, vol.4, no. 2, (2013), pp. 3870-3878.
10. Bhimani Jay, Patel Sandipkumar, Srinivasm Saisivam, “Formulation and Evaluation of
Fast Disintegrating Sublingual Tablets of Ropinirole Hydrochloride”, Int. J. Pharm. Sci.
Rev. Research, vol. 29, no.1, (2014), pp. 268-275.
11. Wetzels GE, Nelemans P, Schouten JS and Pnns MH, “Facts and fiction of poor

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 908

AEGAEUM JOURNAL ISSN NO: 0776-3808

compliance as a cause of Inadequate blood pressure control: A systematic review” , J

Hypertension, vol. 22, (2004), pp. 1849-1855.
12. Kale Sunil, Patil Ameeta and R.H. Mandlecha, “Compliance and Adverse drug Effects
of Antihypertensives in Rural India” , Journal of Clinical and Diagnostic Research, vol.
5, no. 4, (2011), pp. 775-779.
13. Buabeng K. O., Matowe L. and Plange-Rhule J, “Unaffordable drug prices: A major
cause of non-compliance with hypertension medication in Ghana” , J Pharm Phamaceut
Sc., vol. 7, no. 3, (2004), pp. 350 – 352.
14. Carlson E, Chandler W, Galdo I and Kudla T, “Automated integrated forced degradation
and drug-excipients compatibility studies”, J Assoc Lab Autom, vol. 10, (2005), pp. 374-
80.
15. Puttewar TY, Kshirsagar MD, Chandewar AV, Chikhale RV, “Formulation and
evaluation of orodispersible tablet of taste masked doxylamine succinate using ion
exchange resin”, Journal of King Saud University (Science), vol. 22, (2010), pp. 229–
240.
16. Singh I, Kumar P, Nagpal M and Arora S, “Ion-exchange resin complexation: Masking
the bitter taste of cefuroxime axetil”, Cuban Journal of Pharmacy, vol. 45, no.2,
(2011), pp.171-180.
17. Pavia DL, Lampman GM, Kriz GS and Vyvyan JR, “Introduction to Spectroscopy” ,
Cengage Learning India Pvt. Ltd., India, Edition 5, (2015), pp. 37-38.
18. Ziya B, Cetin T, Umut T, Halil E, Cansel K O, Ayhan S and Yalcin O, “Formulation of
Zolmitriptan sublingual tablets prepared by direct compression with different polymers:
In vitro and in vivo evaluation”, European Journal of Pharmaceutics and
Biopharmaceutics, (2011), pp. 499–505.
19. Priyank P, Sandip M, Urvish J, Mihir R, Ankit A and Mandev P, “Sublingual route for
the systemic delivery of Ondansetron”, International Journal of Drug Development &
Research, (2011), pp. 36-44.
20. Aparna B, Kumar B, Gnanaprakash K, Gobinath M and Ramesh Y, “Development and
Evaluation of Sublingual Tablets of Aripiprazole”, International Journal of
Biopharmaceutics, vol. 5, no. 4, (2014), pp. 251-257.
21. Aghera Nikunj, Shah Suresh and Vadalia Kantilal, “Formulation and evaluation of
sublingual tablets of Losartan potassium”, Asian Pacific Journal of Tropical Disease,
vol. 2, no. 1, (2012), pp. S130-S135.
22. Bredenberg Susanne , Duberg Margareta, Lennernas Bo, Lennernas Hans, Pettersson
Anders Westerberg Marie and Nystrom Christer, “In vitro and in vivo evaluation of a
new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as
the active substance”, European Journal of Pharmaceutical Sciences, (2003), pp. 327–
334.
23. Rameshwari S, Sheeba F.R, Acharya G.D and Anandhi J, “Formulation and
evaluation of nifedipine sublingual tablets”, Asian Journal of Pharmaceutical and
Clinical Research, (2009), pp. 44-48.
24. Saadia T, Iman S and Dina L, “Formulation of Ketotifen Fumarate Fast-Melt
Granulation Sublingual Tablet”, AAPS PharmSciTech, (2010), pp. 679–685.
25. Bhanja S, Ellaiah P, Roy H.K, Samal B.K, Tiwari S and Murthy K.V.R, “Formulation
and Evaluation of Perindopril Sublingual Tablets”, International Journal of
Research in Pharmaceutical and Biomedical Sciences, (2011), pp. 1193-1198.

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 909

AEGAEUM JOURNAL ISSN NO: 0776-3808

26. Sahoo Satyajit, Malviya Kirti, Vaidya Santosh Kumar, Golwala Dharmesh and
Mohapatra Prasant Kumar,“Formulation and evaluation of sublingual tablets of
Asenapine maleate by using 32 full factorial design”, Aegaeum Journal, vol. 8, no. 3,
(2020), pp. 1236-1250.
27. Bolton S and Bon C, “Pharmaceutical Statistics: Practical and clinical Applications”,
CRC Press. India, Edition 4, vol. 135, (2007), pp. 506-517.
28. Stability testing of new drug substances and products [Q1A(R2)], “The International
Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH)”, (2003).

Volume 8, Issue 4, 2020 http://aegaeum.com/ Page No: 910