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FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF ASENAPINE
MALEATE BY 32
FULL FACTORIAL DESIGN
Satyajit Sahoo1
*, Kirti Malviya1
, 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.
*1
satyajitccpr@gmail.com
ABSTRACT :
Objectives: The aim of this work was to formulate and evaluate sublingual tablets of Asenapine
maleate for the treatment of schizophrenia and the treatment of manic episodes associated with
bipolar I disorder. Methods: In the present work, the bitter taste of Asenapine maleate was
masked by using Kyron T-114 in 1:1.5 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.Results: 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 54 s. Stability study
was performed by taking an optimized formulation and it was observed stable. The sublingual
tablets showed acceptable results in all studies.Conclusion: The results indicate that the
formulation can be used for the treatment of schizophrenia and the treatment of manic episodes
associated with bipolar I disorder. Moreover, Asenapine maleate as sublingual tablets may
overcome the first pass effect, gives better bioavailability, rapid onset of action and patient
compliance.
Key words: Sublingual tablets, Schizophrenia, Asenapine Maleate, Cross Povidone, Avicel PH
102, Kyron T- 114, 32
full factorial designs
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
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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]
Asenapine is claimed to be
a novel psychopharmacologic agent with high affinity and potency for blocking dopamine,
serotonin, α-adrenergic and histamine receptors and no appreciable activity at muscarinic
cholinergic receptors. The mechanism of action of asenapine, like other atypical antipsychotics is
believed to be mediated through a combination of antagonist activity at 5-HT2A and D2
receptors.[11]
Schizophrenia is a severe, disabling disorder that affects about 1% of the world’s
population. Moreover, schizophrenia is a disorder associated with a high risk of suicidality, with
a frequently reported modal rate of suicide rate being approximately 10%.[12]
Individuals with
bipolar I disorder have a substantially elevated risk of suicidality, with 10-15% of affected
individuals finally committing suicide (DSM-IV-TR). More recently, atypical antipsychotics
have increasingly been used successfully and approved to treat manic episodes associated
with bipolar I disorder.[13]
MATERIALS AND METHODS
Asenapine maleate was obtained from Sun 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 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 Asenapine 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 Asenapine 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
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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 270 nm.
Table 1 : Percentage Drug loading was found in DRC
Ratio of Drug and Resin Percentage Drug Loading
1:1 19.8%
1:1.5 46.4%
1:2 35.86%
1:2.5 29.8%
1:3 28.6%
It was observed that maximum drug loading in DRC was found in 1:1.5 ratio of Drug and Resin.
Preparation of sublingual tablets
Drug Resin complex (DRC) was prepared by using Kyron T114 as a resin. The remaining
ingredients was weighed. 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 Asenapine Maleate
containing various polymers. For the selection of particular polymer various preliminary trial
batches were carried out with Crosspovidone, Sodium starch glycolate and Crosscarmellose
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 25 25 25 25 25 25 25 25 25 25 25 25
Pearlitol SD
200
25 25 25 25 25 25 25 25 25 25 25 25
Avicel PH102 15 20 25 30 15 20 25 30 15 20 25 30
Lactose DCL 25 19 13 7 25 19 13 7 25 19 13 7
Cross
povidone
2 3 4 5 - - - - -
- - -
Sodium Starch
Glycolate
- - - - 2 3 4 5 -
- - -
Cross
Carmelose
Sodium
- - - - - - - - 2 3 4 5
Citric acid 1 1 1 1 1 1 1 1 1 1 1 1
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Aspartame 5 5 5 5 5 5 5 5 5 5 5 5
Talc 2 2 2 2 2 2 2 2 2 2 2 2
Total Weight
(mg)
100 100 100 100 100 100 100 100 100 100 100 100
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 Asenapine 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.
Y = β0 + β1 X1 + β2 X2 + β12 X1 X2 + β11X1
2
+ β22 X2
2
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
Cross Povidone
Concentration of
Avicel PH102
Hardness Disintegration
time
% CDR
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Table 4: Three levels of each variable
Level X1 (% w/v) X2 (% w/v)
Low (-1) 3 15
Medium (0) 4 20
High (+1) 5 25
Table 5: Formulation of Factorial Batches
Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9
DRC 25 25 25 25 25 25 25 25 25
Pearlitol SD
200
25 25 25 25 25 25 25 25 25
Avicel PH102 15 15 15 20 20 20 25 25 25
Lactose DCL 24 23 22 19 18 17 14 13 12
Cross
povidone
3 4 5 3 4 5 3 4 5
Citric acid 1 1 1 1 1 1 1 1 1
Aspartame 5 5 5 5 5 5 5 5 5
Talc 2 2 2 2 2 2 2 2 2
Total Weight
(mg)
100 100 100 100 100 100 100 100 100
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 Asenapine maleate, Kyron T-114,
Cross Povidone, Avicel PH102 and their mixture of Asenapine 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 aromatic C=C, C-0, C-N and C-Cl. 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 Asenapine Maleate, Kyron T-114,
Cross Povidone, Avicel PH102 .[17]
Figure 1.1 FT-IR spectra of Asenapine Maleate Figure 1.2 FT-IR spectra of Drug and Resin
(Asenapine maleate and Kyron T114 )
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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 2.8 to 3.1 mm. [18]
Weight variation
The average weight of tablet formulations was within the range of 98.2±2.08 to 100±2.36 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 2.8±0.15 to 3.2±0.17 kg/cm2
.
This ensure good handling characteristics of all batches. .[20]
% Friability
The % friability of all the batches was between 0.52 to 0.86 % which was less than 1%. So %
friability was within the limit. [21]
Disintegration time
The disintegration time of all the batches was between 54 to 69 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]
Wetting time
The wetting time of all the batches was found to be between 48 to 56 sec. [23]
Drug content
The percentage drug content of the all batches was between 96.98% to 98.02%, which is within
acceptable limits indicate dose uniformity in each batch. [24]
In-vitro dissolution study
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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
(in min)
% Drug Release
F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
3 21.76 19.11 18.36 25.6 26.96 25.8 24.12 25.72 25.88
6 45.6 41.42 38.98 52.18 54.7 52.36 49.9 50.7 52.8
9 68.9 58.64 59.36 70.98 72.2 70.9 64.2 72.3 71.86
12 86.2 79.52 75.2 85.7 90.4 88.2 81.46 83.78 88.2
15 92.9 87.96 85.3 95.2 98.02 96.6 91.9 94.96 96.8
Figure 2: Drug release profile of batch F1-F9
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 15 min.
of Asenapine maleate (Y3) were selected as dependent variables. Table 7 shows list of
variables.
The polynomial equation for 32
factorial designs is described as follows:
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Y = β0 + β1X1 + β2X2+ β12 X1 X2+ β11X1
2
+ β22X2
2
…………………………………..(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 (X1
2
and
X2
2
) are included to investigate nonlinearity [26,27]
.
Table 7: Experimental runs and measured responses
Batch
X1
(conc. of Cross
Povidone)
X2
(conc. of
Avicel
PH102)
Y1
Hardness
(kg/cm2
)
Y2
Disintegr
ation
time (sec)
Y3
% Cumulative
Drug release
after 25 min.
F1 -1 -1 2.8±0.10 62±0.20 92.9
F2 0 -1 2.9±0.50 59±1.06 87.9
F3 +1 -1 3.1±0.24 61±0.40 85.3
F4 -1 0 2.8±0.36 63±1.28 95.2
F5 0 0 3.0±0.40 54±0.20 98.2
F6 +1 0 3.1±0.25 58±1.30 96.6
F7 -1 +1 2.9±0.64 69±0.10 91.8
F8 0 +1 3.1±0.80 62±0.50 94.6
F9 +1 +1 3.2±0.18 65±1.80 96.8
The fitted equations (full model) relating the responses that is, hardness (Y1), disintegration time
(Y2) and % cumulative drug release after 15 min. of Asenapine 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
Asenapine maleate (Y3) were 0.9737, 0.9485 and 0.9585 respectively indicating good correlation
between dependent and independent variables. There was no need to develop reduced models
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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 Asenapine maleate (Y3) were 22.20, 11.05 and13.87
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
(Y1)
β0 β1 β2 β12 β11 Β22 R2
value
Coefficient +2.98 +0.15 +0.07 -1.53 -0.02 0.03
0.9737
P Value 0.0142 0.0024 0.0240 1.000 0.5836 0.3081
Disintegration time (sec)
Response
(Y2)
β0 β1 β2 β12 β11 Β22 R2
value
Coefficient +55.22 -1.67 +2.33 -0.75 +4.67 +4.67
0.9485
P Value 0.0378 0.0820 0.0366 0.4135 0.0252 0.0252
Cumulative Drug release after 15 min. (%) of Asenapine maleate
Response
(Y3)
β0 β1 β2 β12 β11 Β22 R2
value
Coefficient +96.96 -0.22 +2.92 +3.12 -0.53 -4.97
0.9585
P Value 0.0276 0.7339 0.0152 0.0218 0.6347 0.0159
Table 9: Results of the ANOVA for dependent variables
Source of
Variation
DF SS MS F P
Hardness (kg/cm2
)
Regression 5 0.16 0.033
22.20 0.0142
Residual 3 0.01 0.001
Total 8 0.17 0.034
Disintegration time (sec)
Regression 5 138.69 27.74
18.24 0.0378
Residual 3 7.53 2.51
Total 8 146.22 30.25
Cumulative Drug release after 15 min. (%) of Asenapine maleate
Regression 5 140.35 28.07
13.87 0.0276
Residual 3 6.07 2.02
Total 8 146.42 30.09
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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, β11 and β22 were found to have P
value of 1.000, 0.5836 and 0.3081. So, it was omitted from the full model to generate a reduced
model. The coefficients β0, β1 andβ2 and were found to be significant at P < 0.05. Hence, they
were retained in the reduced model.
The reduced model for Hardness was:
Hardness = +2.98 + 0.15*X1 + 0.07*X2
Design-Expert® Software
Hardness
Design Points
3.2
2.8
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00 -0.50 0.00 0.50 1.00
-1.00
-0.50
0.00
0.50
1.00
Hardness
A: conc. of Cross Povidone
B:
conc.
of
Avicel
PH102
2.85
2.92222 2.99444 3.06667
3.13889
Fig 3.1 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on Hardness
(Y1)
Design-Expert® Software
Hardness
Design points above predicted value
Design points below predicted value
3.2
2.8
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00
-0.50
0.00
0.50
1.00
-1.00
-0.50
0.00
0.50
1.00
2.77
2.8825
2.995
3.1075
3.22
Hardness
A: conc. of Cross Povidone
B: conc. of Avicel PH102
Fig 3.2 : Response surface plot showing the effect of
Cross Povidone (X1) and Avicel PH 102 (X2) on
Hardness (Y1)
Full and reduced model for Disintegration time of Asenapine 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 and β2 were found to have P
value of 0.0820 and 0.4135. So, it was omitted from the full model to generate a reduced model.
The coefficients β0, β12, 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 = +55.22 + 2.33*X2 + 4.67*X1
2
+ 4.67*X2
2
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Design-Expert® Software
Disintegration time
Design Points
69
54
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00 -0.50 0.00 0.50 1.00
-1.00
-0.50
0.00
0.50
1.00
Disintegration time
A: conc. of Cross Povidone
B:
conc.
of
Avicel
PH102
57.229
59.6443
59.6443
62.0596
62.0596
62.0596
64.4749
66.8902
Fig 4.1 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on Disintegration
time (Y2)
Design-Expert® Software
Disintegration time
Design points above predicted value
Design points below predicted value
69
54
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00
-0.50
0.00
0.50
1.00
-1.00
-0.50
0.00
0.50
1.00
54
58
62
66
70
Disintegration
time
A: conc. of Cross Povidone
B: conc. of Avicel PH102
Fig 4.2 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on
Disintegration 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 β1 and β11 were found to have P
value of 0.7339 and 0.6347. So, it was omitted from the full model to generate a reduced model.
The coefficients β0, β2 , β12 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 = +96.96 + 2.92*X2 + 3.12*X1X2 - 4.97*X2
2
Design-Expert® Software
%CDR
Design Points
98.02
85.3
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00 -0.50 0.00 0.50 1.00
-1.00
-0.50
0.00
0.50
1.00
%CDR
A: conc. of Cross Povidone
B:
conc.
of
Avicel
PH102
87.3429
89.4842
91.6254
93.7666
93.7666
95.9079
95.9079
Fig 5.1 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on % CDR
(Y3)
Design-Expert® Software
%CDR
Design points above predicted value
Design points below predicted value
98.02
85.3
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00
-0.50
0.00
0.50
1.00
-1.00
-0.50
0.00
0.50
1.00
85
88.5
92
95.5
99
%CDR
A: conc. of Cross Povidone
B: conc. of Avicel PH102
Fig 5.2 : Contour plot showing the effect of Cross
Povidone (X1) and Avicel PH 102 (X2) on %CDR (Y3)
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
AEGAEUM JOURNAL
Volume 8, Issue 3, 2020
ISSN NO: 0776-3808
http://aegaeum.com/ Page No: 1246
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
Overlay Plot
Hardness
Disintegration time
%CDR
Design Points
X1 = A: conc. of Cross Povidone
X2 = B: conc. of Avicel PH102
-1.00 -0.50 0.00 0.50 1.00
-1.00
-0.50
0.00
0.50
1.00
Overlay Plot
A: conc. of Cross Povidone
B:
conc.
of
Avicel
PH102 Hardness: 2.9
Hardness: 3.1
Disintegrationtim
e: 56
%CDR: 86
%CDR: 95
%CDR: 95
Hardness: 3.06608
Disintegration 56.4734
%CDR: 94.7631
X1 0.75
X2 -0.26
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)
+0.75 -0.26 4.75 16.25
Table 11: Results of Check point batch method
Response Predicted value Experimental value
Hardness (kg/cm2
) 3.066 2.948
Disintegration time (sec) 56.473 58.650
% CDR at 15 min. of Asenapine
maleate
94.763 91.960
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 40o
C and at
75% ± 5 RH conditions. From stability studies it was concluded that the sublingual tablets of
Asenapine maleate was stable [28]
.
Table 12: Result of short term stability study of optimized batch
Evaluation Parameters Before Stability period After Stability period
Hardness (kg/cm2
) 3.0±0.40 2.9±0.60
Disintegration time(sec) 54±0.20 52±0.45
% CDR at 15 min 98.2 97.52
AEGAEUM JOURNAL
Volume 8, Issue 3, 2020
ISSN NO: 0776-3808
http://aegaeum.com/ Page No: 1247
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 bitter taste of Asenapine 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 20 % 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 Asenapine
maleate tablets.
CONCLUSION
Sublingual tablets of Asenapine maleate were prepared by direct compression method. Firstly,
the bitter taste of Asenapine maleate was masked by using Kyron T-114 in 1:1.5 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
3.0±0.40, disintegration time 54 sec and percentage cumulative drug release was found 98.2 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
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
Asenapine maleate. Sodium starch glycolate and Avicel PH102 were obtained from Chemdyes
AEGAEUM JOURNAL
Volume 8, Issue 3, 2020
ISSN NO: 0776-3808
http://aegaeum.com/ Page No: 1248
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.
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Formulation and Evaluation of Sublingual Tablets of Asenapine Maleate By 32 Full Factorial Design.pdf

  • 1. FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF ASENAPINE MALEATE BY 32 FULL FACTORIAL DESIGN Satyajit Sahoo1 *, Kirti Malviya1 , 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. *1 satyajitccpr@gmail.com ABSTRACT : Objectives: The aim of this work was to formulate and evaluate sublingual tablets of Asenapine maleate for the treatment of schizophrenia and the treatment of manic episodes associated with bipolar I disorder. Methods: In the present work, the bitter taste of Asenapine maleate was masked by using Kyron T-114 in 1:1.5 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.Results: 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 54 s. Stability study was performed by taking an optimized formulation and it was observed stable. The sublingual tablets showed acceptable results in all studies.Conclusion: The results indicate that the formulation can be used for the treatment of schizophrenia and the treatment of manic episodes associated with bipolar I disorder. Moreover, Asenapine maleate as sublingual tablets may overcome the first pass effect, gives better bioavailability, rapid onset of action and patient compliance. Key words: Sublingual tablets, Schizophrenia, Asenapine Maleate, Cross Povidone, Avicel PH 102, Kyron T- 114, 32 full factorial designs 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 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1236
  • 2. 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] Asenapine is claimed to be a novel psychopharmacologic agent with high affinity and potency for blocking dopamine, serotonin, α-adrenergic and histamine receptors and no appreciable activity at muscarinic cholinergic receptors. The mechanism of action of asenapine, like other atypical antipsychotics is believed to be mediated through a combination of antagonist activity at 5-HT2A and D2 receptors.[11] Schizophrenia is a severe, disabling disorder that affects about 1% of the world’s population. Moreover, schizophrenia is a disorder associated with a high risk of suicidality, with a frequently reported modal rate of suicide rate being approximately 10%.[12] Individuals with bipolar I disorder have a substantially elevated risk of suicidality, with 10-15% of affected individuals finally committing suicide (DSM-IV-TR). More recently, atypical antipsychotics have increasingly been used successfully and approved to treat manic episodes associated with bipolar I disorder.[13] MATERIALS AND METHODS Asenapine maleate was obtained from Sun 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 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 Asenapine 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 Asenapine 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 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1237
  • 3. 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 270 nm. Table 1 : Percentage Drug loading was found in DRC Ratio of Drug and Resin Percentage Drug Loading 1:1 19.8% 1:1.5 46.4% 1:2 35.86% 1:2.5 29.8% 1:3 28.6% It was observed that maximum drug loading in DRC was found in 1:1.5 ratio of Drug and Resin. Preparation of sublingual tablets Drug Resin complex (DRC) was prepared by using Kyron T114 as a resin. The remaining ingredients was weighed. 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 Asenapine Maleate containing various polymers. For the selection of particular polymer various preliminary trial batches were carried out with Crosspovidone, Sodium starch glycolate and Crosscarmellose 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 25 25 25 25 25 25 25 25 25 25 25 25 Pearlitol SD 200 25 25 25 25 25 25 25 25 25 25 25 25 Avicel PH102 15 20 25 30 15 20 25 30 15 20 25 30 Lactose DCL 25 19 13 7 25 19 13 7 25 19 13 7 Cross povidone 2 3 4 5 - - - - - - - - Sodium Starch Glycolate - - - - 2 3 4 5 - - - - Cross Carmelose Sodium - - - - - - - - 2 3 4 5 Citric acid 1 1 1 1 1 1 1 1 1 1 1 1 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1238
  • 4. Aspartame 5 5 5 5 5 5 5 5 5 5 5 5 Talc 2 2 2 2 2 2 2 2 2 2 2 2 Total Weight (mg) 100 100 100 100 100 100 100 100 100 100 100 100 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 Asenapine 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. Y = β0 + β1 X1 + β2 X2 + β12 X1 X2 + β11X1 2 + β22 X2 2 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 Cross Povidone Concentration of Avicel PH102 Hardness Disintegration time % CDR AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1239
  • 5. Table 4: Three levels of each variable Level X1 (% w/v) X2 (% w/v) Low (-1) 3 15 Medium (0) 4 20 High (+1) 5 25 Table 5: Formulation of Factorial Batches Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 DRC 25 25 25 25 25 25 25 25 25 Pearlitol SD 200 25 25 25 25 25 25 25 25 25 Avicel PH102 15 15 15 20 20 20 25 25 25 Lactose DCL 24 23 22 19 18 17 14 13 12 Cross povidone 3 4 5 3 4 5 3 4 5 Citric acid 1 1 1 1 1 1 1 1 1 Aspartame 5 5 5 5 5 5 5 5 5 Talc 2 2 2 2 2 2 2 2 2 Total Weight (mg) 100 100 100 100 100 100 100 100 100 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 Asenapine maleate, Kyron T-114, Cross Povidone, Avicel PH102 and their mixture of Asenapine 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 aromatic C=C, C-0, C-N and C-Cl. 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 Asenapine Maleate, Kyron T-114, Cross Povidone, Avicel PH102 .[17] Figure 1.1 FT-IR spectra of Asenapine Maleate Figure 1.2 FT-IR spectra of Drug and Resin (Asenapine maleate and Kyron T114 ) AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1240
  • 6. 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 2.8 to 3.1 mm. [18] Weight variation The average weight of tablet formulations was within the range of 98.2±2.08 to 100±2.36 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 2.8±0.15 to 3.2±0.17 kg/cm2 . This ensure good handling characteristics of all batches. .[20] % Friability The % friability of all the batches was between 0.52 to 0.86 % which was less than 1%. So % friability was within the limit. [21] Disintegration time The disintegration time of all the batches was between 54 to 69 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] Wetting time The wetting time of all the batches was found to be between 48 to 56 sec. [23] Drug content The percentage drug content of the all batches was between 96.98% to 98.02%, which is within acceptable limits indicate dose uniformity in each batch. [24] In-vitro dissolution study AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1241
  • 7. 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 (in min) % Drug Release F1 F2 F3 F4 F5 F6 F7 F8 F9 0 0 0 0 0 0 0 0 0 0 3 21.76 19.11 18.36 25.6 26.96 25.8 24.12 25.72 25.88 6 45.6 41.42 38.98 52.18 54.7 52.36 49.9 50.7 52.8 9 68.9 58.64 59.36 70.98 72.2 70.9 64.2 72.3 71.86 12 86.2 79.52 75.2 85.7 90.4 88.2 81.46 83.78 88.2 15 92.9 87.96 85.3 95.2 98.02 96.6 91.9 94.96 96.8 Figure 2: Drug release profile of batch F1-F9 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 15 min. of Asenapine maleate (Y3) were selected as dependent variables. Table 7 shows list of variables. The polynomial equation for 32 factorial designs is described as follows: AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1242
  • 8. Y = β0 + β1X1 + β2X2+ β12 X1 X2+ β11X1 2 + β22X2 2 …………………………………..(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 (X1 2 and X2 2 ) are included to investigate nonlinearity [26,27] . Table 7: Experimental runs and measured responses Batch X1 (conc. of Cross Povidone) X2 (conc. of Avicel PH102) Y1 Hardness (kg/cm2 ) Y2 Disintegr ation time (sec) Y3 % Cumulative Drug release after 25 min. F1 -1 -1 2.8±0.10 62±0.20 92.9 F2 0 -1 2.9±0.50 59±1.06 87.9 F3 +1 -1 3.1±0.24 61±0.40 85.3 F4 -1 0 2.8±0.36 63±1.28 95.2 F5 0 0 3.0±0.40 54±0.20 98.2 F6 +1 0 3.1±0.25 58±1.30 96.6 F7 -1 +1 2.9±0.64 69±0.10 91.8 F8 0 +1 3.1±0.80 62±0.50 94.6 F9 +1 +1 3.2±0.18 65±1.80 96.8 The fitted equations (full model) relating the responses that is, hardness (Y1), disintegration time (Y2) and % cumulative drug release after 15 min. of Asenapine 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 Asenapine maleate (Y3) were 0.9737, 0.9485 and 0.9585 respectively indicating good correlation between dependent and independent variables. There was no need to develop reduced models AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1243
  • 9. 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 Asenapine maleate (Y3) were 22.20, 11.05 and13.87 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 (Y1) β0 β1 β2 β12 β11 Β22 R2 value Coefficient +2.98 +0.15 +0.07 -1.53 -0.02 0.03 0.9737 P Value 0.0142 0.0024 0.0240 1.000 0.5836 0.3081 Disintegration time (sec) Response (Y2) β0 β1 β2 β12 β11 Β22 R2 value Coefficient +55.22 -1.67 +2.33 -0.75 +4.67 +4.67 0.9485 P Value 0.0378 0.0820 0.0366 0.4135 0.0252 0.0252 Cumulative Drug release after 15 min. (%) of Asenapine maleate Response (Y3) β0 β1 β2 β12 β11 Β22 R2 value Coefficient +96.96 -0.22 +2.92 +3.12 -0.53 -4.97 0.9585 P Value 0.0276 0.7339 0.0152 0.0218 0.6347 0.0159 Table 9: Results of the ANOVA for dependent variables Source of Variation DF SS MS F P Hardness (kg/cm2 ) Regression 5 0.16 0.033 22.20 0.0142 Residual 3 0.01 0.001 Total 8 0.17 0.034 Disintegration time (sec) Regression 5 138.69 27.74 18.24 0.0378 Residual 3 7.53 2.51 Total 8 146.22 30.25 Cumulative Drug release after 15 min. (%) of Asenapine maleate Regression 5 140.35 28.07 13.87 0.0276 Residual 3 6.07 2.02 Total 8 146.42 30.09 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1244
  • 10. 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, β11 and β22 were found to have P value of 1.000, 0.5836 and 0.3081. So, it was omitted from the full model to generate a reduced model. The coefficients β0, β1 andβ2 and were found to be significant at P < 0.05. Hence, they were retained in the reduced model. The reduced model for Hardness was: Hardness = +2.98 + 0.15*X1 + 0.07*X2 Design-Expert® Software Hardness Design Points 3.2 2.8 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 Hardness A: conc. of Cross Povidone B: conc. of Avicel PH102 2.85 2.92222 2.99444 3.06667 3.13889 Fig 3.1 : Contour plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on Hardness (Y1) Design-Expert® Software Hardness Design points above predicted value Design points below predicted value 3.2 2.8 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 2.77 2.8825 2.995 3.1075 3.22 Hardness A: conc. of Cross Povidone B: conc. of Avicel PH102 Fig 3.2 : Response surface plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on Hardness (Y1) Full and reduced model for Disintegration time of Asenapine 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 and β2 were found to have P value of 0.0820 and 0.4135. So, it was omitted from the full model to generate a reduced model. The coefficients β0, β12, 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 = +55.22 + 2.33*X2 + 4.67*X1 2 + 4.67*X2 2 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1245
  • 11. Design-Expert® Software Disintegration time Design Points 69 54 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 Disintegration time A: conc. of Cross Povidone B: conc. of Avicel PH102 57.229 59.6443 59.6443 62.0596 62.0596 62.0596 64.4749 66.8902 Fig 4.1 : Contour plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on Disintegration time (Y2) Design-Expert® Software Disintegration time Design points above predicted value Design points below predicted value 69 54 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 54 58 62 66 70 Disintegration time A: conc. of Cross Povidone B: conc. of Avicel PH102 Fig 4.2 : Contour plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on Disintegration 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 β1 and β11 were found to have P value of 0.7339 and 0.6347. So, it was omitted from the full model to generate a reduced model. The coefficients β0, β2 , β12 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 = +96.96 + 2.92*X2 + 3.12*X1X2 - 4.97*X2 2 Design-Expert® Software %CDR Design Points 98.02 85.3 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 %CDR A: conc. of Cross Povidone B: conc. of Avicel PH102 87.3429 89.4842 91.6254 93.7666 93.7666 95.9079 95.9079 Fig 5.1 : Contour plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on % CDR (Y3) Design-Expert® Software %CDR Design points above predicted value Design points below predicted value 98.02 85.3 X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 85 88.5 92 95.5 99 %CDR A: conc. of Cross Povidone B: conc. of Avicel PH102 Fig 5.2 : Contour plot showing the effect of Cross Povidone (X1) and Avicel PH 102 (X2) on %CDR (Y3) 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 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1246
  • 12. 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 Overlay Plot Hardness Disintegration time %CDR Design Points X1 = A: conc. of Cross Povidone X2 = B: conc. of Avicel PH102 -1.00 -0.50 0.00 0.50 1.00 -1.00 -0.50 0.00 0.50 1.00 Overlay Plot A: conc. of Cross Povidone B: conc. of Avicel PH102 Hardness: 2.9 Hardness: 3.1 Disintegrationtim e: 56 %CDR: 86 %CDR: 95 %CDR: 95 Hardness: 3.06608 Disintegration 56.4734 %CDR: 94.7631 X1 0.75 X2 -0.26 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) +0.75 -0.26 4.75 16.25 Table 11: Results of Check point batch method Response Predicted value Experimental value Hardness (kg/cm2 ) 3.066 2.948 Disintegration time (sec) 56.473 58.650 % CDR at 15 min. of Asenapine maleate 94.763 91.960 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 40o C and at 75% ± 5 RH conditions. From stability studies it was concluded that the sublingual tablets of Asenapine maleate was stable [28] . Table 12: Result of short term stability study of optimized batch Evaluation Parameters Before Stability period After Stability period Hardness (kg/cm2 ) 3.0±0.40 2.9±0.60 Disintegration time(sec) 54±0.20 52±0.45 % CDR at 15 min 98.2 97.52 AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1247
  • 13. 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 bitter taste of Asenapine 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 20 % 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 Asenapine maleate tablets. CONCLUSION Sublingual tablets of Asenapine maleate were prepared by direct compression method. Firstly, the bitter taste of Asenapine maleate was masked by using Kyron T-114 in 1:1.5 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 3.0±0.40, disintegration time 54 sec and percentage cumulative drug release was found 98.2 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 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 Asenapine maleate. Sodium starch glycolate and Avicel PH102 were obtained from Chemdyes AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1248
  • 14. 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, 2012; vol. 2, (2012), pp. S130-S135. 3. M.D. Nehal Siddiqui, Garg Garima and Sharma Pramod Kumar, “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 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 and Pancholi SS, “Sublingual route for systemic drug delivery: A Pharmaceuitical 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, 2013; vol. 4, no.2, (2013), pp. 3870-3878. 10. Bhimani Jay, Patel Sandipkumar and 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. Eugen D and Markus G. “Asenapine maleate In The Treatment of Opioid Dependence European Neuropsychopharmacology”, Elsevier, vol. 14, (2004), pp. 209–216. 12. Rolley E and Eric C, “Asenapine maleate: How To Use It Right Drug And Alcohol Dependence”, Elesevier, vol. 70, (2003), pp. 59-77. 13. Jason W and James B, Saund, “Open Label Dose Finding Trial of Asenapine maleate for Implant Treatment Of Heroin Dependence Drug And Alcohol Dependence” Elesevier vol. 103 (2009), pp. 37–43. AEGAEUM JOURNAL Volume 8, Issue 3, 2020 ISSN NO: 0776-3808 http://aegaeum.com/ Page No: 1249
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