Formulation Development and Evaluation of Doxofylline Sustained Release Tablets

FABAD J. Pharm. Sci., 42, 3, 199-208, 2017
Formulation Development and Evaluation of Doxofylline
Sustained ReleaseTablets
Raghavendra KUMAR GUNDA*º
, Jujjuru Naga Suresh KUMAR*
RESEARCH ARTICLE
199
*
Department of Pharmaceutics, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur (Dt), Andhra Pradesh, India-522601
° Corresponding Author;
M.Pharm.,(Ph.D), Assistant Professor, Department of Pharmaceutics,
Narasaraopeta Institute of Pharmaceutical Sciences,
Narasaraopet, Guntur (D.t), A.P. India-522601.
E-mail: raghav.gunda@gmail.com,
Mob: +91-9666705894
Formulation Development And Evaluation Of Doxofylline
Sustained Release Tablets
SUMMARY
The main objective of present research investigation is to formulate
the sustained release tablet of Doxofylline using 32
factorial design.
Doxofylline, an anti-Asthmatic agent, belongs BCS class-III agent.
The SR tablets of Doxofylline were prepared employing different
concentrations of HPMC K100M and Chitosan in different
combinations by Direct Compression technique using 32
factorial
design. The concentration of Polymers, HPMC K100M and
Chitosan required to achieve the desired drug release was selected as
independent variables, X1
and X2
respectively whereas, time required
for 10% of drug dissolution (t10%
), 50% (t50%
), 75% (t75%
) and 90%
(t90%
) were selected as dependent variables. Totally nine formulations
were designed, Formulated and are evaluated for hardness, friability,
thickness, % drug content, In-vitro drug release. From the Results
it was concluded that all the formulation were found to be with
in the Pharmacopoeial limits and the In-vitro dissolution profiles
of all formulations were fitted in to different Kinetic models, the
statistical parameters like intercept, slope & regression coefficient
were calculated. Polynomial equations were developed for t10%
,
t50%
, t75%
, t90%. Validity of developed polynomial equations were
verified by designing 2 check point formulations (C1
, C2
). According
to SUPAC guidelines the formulation (F4
) containing combination
of 10% HPMC K100M and 15% Chitosan, is the most similar
formulation (similarity factor f2
= 64.501, dissimilarity factor f1
=
6.862 & No significant difference, t= 0.23001) to marketed product
(DOXOLIN). The selected formulation (F4
) follows Zero order,
Higuchi’s kinetics, and the mechanism of drug release was found to
be Non-Fickian Diffusion anomalous Super Case-II Transport (n=
0.963).
Key Words: Doxofylline, 32 Factorial Design, Sustained Release
Tablet, HPMC K100M ,Chitosan, SUPAC,
Received: 23.08.2017
Revised: 03.10.2017
Accepted: 04.10.2017
Doksofilin Sürekli Salım Tablet Formülasyonu Geliştirme ve
Değerlendirme
ÖZET
Bu araştırma makalesinin temel amacı, 32
faktöriyel tasarım
kullanarak Doksofilin’in sürekli salım tablet formülasyonunu
geliştirmektir. Doksofilin, astıma karşı kullanılan, BCS sınıf III’e
ait bir bileşiktir. Doksofilin’in SR tabletleri, 32
faktöriyel tasarım
kullanılarak direk basım tekniği ile farklı konsantrasyonlarda
HPMC K100M ve kitozan kullanılarak farklı kombinasyonlarda
hazırlanmıştır. İstenen ilaç salımını sağlamak için gereken HPMC
K100M ve kitozan polimerlerin konsantrasyonu, ilaç çözünmesinin
%10’u (t10%
), %50 (t50%
), %75 (t75%
) ‘i (t50%
) olmak üzere bağımsız
değişkenler X1
ve X2
olarak seçilmiştir ve %90 (t90%
) bağımlı
değişken olarak seçilmiştir. Dokuz formülasyon tasarlanmış, formüle
edilmiş ve sertlik, ufalanabilirlik, kalınlık, % ilaç içeriği, in-
vitro ilaç salımı değerlendirilmiştir. Sonuçlara bakıldığında, tüm
formülasyonların Farmakope limitleri içinde olduğu bulunmuştur
ve tüm formülasyonların in-vitro çözünme profilleri farklı kinetik
modellere uydurulmuş, kesişim, eğim ve regresyon katsayısı gibi
istatistiksel parametreler hesaplanmıştır. Polinomiyal denklemler
t10%
, t50%
, t75%
, t90%
için geliştirilmiştir. Geliştirilmiş polinom
denklemlerinin geçerliliği, 2 kontrol noktası formülasyonu (C1
,
C2
) tasarlayarak doğrulanmıştır. SUPAC kılavuzlarına göre, %10
HPMC K100M ve %15 kitozan içeren formülasyon (F4
) pazarlanmış
ürüne (DOXOLIN) en benzer formülasyondur (benzerlik faktörü
f2
= 64.501, farklılık faktörü f1 = 6.862 ve anlamlı fark yok, t =
0.23001). Seçilen formülasyon (F4
) sıfırıncı derece kinetik, Higuchi
kinetiği ve ilaç salım mekanizması Non-Fickian Diffüzyon Super
Case II Transport olarak bulunmuştur (n = 0.963).
Anahtar Kelimeler: Doksofilin, 32 Faktöriyel Tasarım, Sürekli
Salım Tableti, HPMC K100M, Kitozan, SUPAC,

200
Kumar Gunda, Kumar
INTRODUCTION
Tabletsarethemostpopularoralsolidformulations
available in the market and are preferred by patients
and physicians alike. There are many reasons for this,
not the least of which would include acceptance by
the patient and ease of administration. In case for the
treatment of chronic disease conditions, conventional
formulations are required to be administered
in multiple doses and therefore have several
disadvantages (Swati Jain et al., 2014). However,
when administered orally, many therapeutic agents
are subjected to extensive presystemic elimination
by gastrointestinal degradation and/or first pass
hepatic metabolism as a result of which low systemic
bioavailability and shorter duration of therapeutic
activity and formation of inactive or toxic metabolites
(R. Ruben Singh., 2014).
Sustained release (SR) tablet formulations are
preferred for such therapy because they offer better
patient compliance, maintain uniform drug levels,
reduce dose and side effects, and increase the safety
margin for high-potency drugs (Raghavendra Kumar
Gundaetal.,2015).Sustainedreleasesystemsgenerally
do not attain this type of release and usually try to
mimic zero-order release by providing drug in a slow
first-order fashion (i. e., concentration dependent).
Systems that are designated as prolonged release can
also be considered as attempts at achieving sustained
release delivery (Lachmann et al., 1991; Bankar GS et
al., 1996; Raghavendra Kumar Gunda et al., 2015).
Sustained release tablet allowing a 2 fold or
greater reduction in frequency of administration of a
drug in comparison with the frequency required by
a prompt release dosage form ( J. N. Suresh Kumar
et al., 2015). Sustained release products provide
advantage over immediate release dosage form by
optimising biopharmaceutical, pharmacokinetic and
pharmacodynamic properties of drug. Sustained
release dosage forms have been demonstrated to
improve therapeutic efficiency by maintenance of a
steady drug plasma concentration.
The use of polymers in controlling the release
of drugs has become an important tool in the
formulation of pharmaceutical dosage forms. Over
many years, numerous studies have been reported
in the literature on the application of hydrophilic
polymers in the development of SR matrix systems for
various drugs ( Raghavendra Kumar Gunda ., 2015).
Since the early 1950s, the application of polymeric
materials for medical purposes is growing very fast.
Polymers have been used in the medical field for a
large extent (Raghavendra Kumar Gunda et al., 2015).
Natural polymers remain attractive primarily because
they are economic, readily available, be capable
of chemical modifications, non-carcinogenicity,
mucoadhesivity, biodegradable, biocompatible, high
drug holding capacity and high thermal stability
and easy of compression (Prakash P et al., 2011).
This led to its application as excipient in hydrophilic
drug delivery system. The various natural gums
and mucilages have been examined as polymers for
sustained drug release in the last few decades for
example; guar gum, tragacanth gum, xanthan gum,
pectin, alginates, Chitosan etc. In the development of
a sustained release tablet dosage form. Availability of
wide variety of polymer and frequent dosing interval
helpsthescientisttodevelopsustainedreleaseproduct.
cellulose derivatives such as carboxymethyl cellulose
(CMC), sodium carboxy methyl cellulose(SCMC),
hydroxyproyl cellulose (HPC), and hydroxypropyl
methyl cellulose (HPMC) have been extensively
studied as polymer in the sustained release tablet
formulations. These polymers are most preferred
because of its cost effectiveness, broad regulatory
acceptance, non-toxic and easy of compression.
Some factors like molecular size, diffusivity, pKa-
ionization constant, release rate, dose and stability,
duration of action, absorption window, therapeutic
index, protein binding, and metabolism affect the
design of sustained release formulation. The future of
sustained release products is promising in some area
like chronopharmacokinetic system, targeted drug
delivery system, mucoadhesive system, particulate
system that provide high promise and acceptability.
Oral sustained release dosage form by direct
compression technique is a simple approach of
drug delivery systems that proved to be rational in
the pharmaceutical arena for its ease, compliance,
faster production, avoid hydrolytic or oxidative
reactions occurred during processing of dosage forms
( Raghavendra Kumar Gunda ., 2015). The selection
of the drug candidates for sustained release system
needs consideration of several biopharmaceutical,
pharmacokinetic and pharmacodynamic properties
of drug molecule (Rhodes C.T et al., 2003).
In the present study, a sustained release dosage
form of Doxofylline has been developed that makes
less frequent administering of drug.
Doxofylline, a new generation methyl xanthine
derivative used to treat Asthma, belongs BCS class-III
agent. It acts by inhibiting Phosphodiesterase there by
producing Bronchodilator activity . It has decreased
affinity towards A1
, A2
receptors (P. Praveen kumar

201
FABAD J. Pharm. Sci., 42, 3, 199-208, 2017
et al., 2014). After oral administration, shows peak
plasma level within one hour. Absolute Bioavailability
is 62.59% protein binding about 48%. Less than 4% of
oral dose excreted unchanged in Urine (Kaushik P et
al., 2012). The poor aqueous solubility and wettability
of Doxofylline give rise to difficulties in the design
of pharmaceutical formulations and led to variable
oral bioavailability. Thus, there is a need to increase
rate of dissolution. Hence, the study was carried out
to formulate and evaluate sustained release dosage
form of Doxofylline as a model drug and had an aim
that final batch formulation parameters should shows
prolong drug release.
It is an important issue is to design an optimized
formulation with an appropriate dissolution rate
in a short time period and minimum trials. Many
statistical experimental designs have been recognized
as useful techniques to optimize the process variables.
For this purpose, response surface methodology
(RSM) utilizing a polynomial equation has been
widely used. Different types of RSM designs include
3-level factorial design, central composite design
(CCD), Box-Behnken design and D-optimal design.
Response surface methodology (RSM) is used
when only a few significant factors are involved in
experimental optimization. The technique requires
less experimentation and time, thus proving to be far
more effective and cost-effective than the conventional
methods of formulating sustained release dosage
forms (Raghavendra Kumar Gunda ., 2016).
Hence an attempt is made in this research work to
formulate sustained release (SR) tablets of Doxofylline
using HPMC K100M and Chitosan . Instead of
normal and trial method, a standard statistical tool
design of experiments is employed to study the effect
of formulation variables on the release properties.
Large scale production needs more simplicity in the
formulation with economic and cheapest dosage form.
A 32
full factorial design was employed to
systematically study the drug release profile . A 32
full
factorial design was employed to investigate the effect
of two independent variables (factors), i.e the amounts
of HPMC K100M and Chitosan on the dependent
variables, i.e. t10%
, t50%
, t75%
, t90%
,(Time taken to release
10%,50%,75%,90% respectively).
MATERIALS AND METHODS
Materials used in this study were obtained from
the different sources. Doxofylline was a gift sample
from Aurobindo pharma Ltd, Hyderabad, India.
HPMC K100M, Chitosan were procured from Merck
Specialities Pvt.Ltd , Mumbai. Micro crystalline
cellulose, PVP K30 were procured from Loba Chemie
Pvt.Ltd, Mumbai. Other excipients such as magnesium
stearate, Talc were procured from S.D. Fine Chem.
Ltd., Mumbai.
Formulation Development of Doxofylline
Sustained Release Tablets:
The factorial design is a technique that allows
identification of factors involved in a process and
assesses their relative importance. In addition, any
interaction between factors chosen can be identified.
Construction of a factorial design involves the
selection of parameters and the choice of responses
(Raghavendra Kumar et al., 2015; Raghavendra
Kumar et al., 2016).
A selected three level, two factor experimental
design (32
factorial design) describe the proportion
in which the independent variables HPMC K100M
and chitosan were used in formulation of Doxofylline
sustained release (SR) Tablets. The time required for
10% (t10%
), 50% (t50%
), 75% (t75%
) and 90% (t90%
) drug
dissolution were selected as dependent variables.
Significance terms were chosen at 95% confidence
interval (p<0.05) for Final Equations. Polynomial
equations were developed for t10%
, t50%
, t75%
, t90%
,(step-
wise backward Linear Regression Analysis).
The three levels of factor X1
(HPMC K100M)
at a concentration of 5%, 10%, 15%. three levels of
factor X2
(Chitosan) at a concentration of 5%, 10%,
15%.(% with respect to total tablet weight) was taken
as the rationale for the design of the Doxofylline
SR tablet formulation. nine Doxofylline sustained
release tablet formulations were prepared employing
selected combinations of the two factors i.e X1
, X2
as per 32
Factorial and evaluated to find out the
significance of combined effects of X1
, X2
to select the
best combination and the concentration required to
achieve the desired prolonged/ sustained release of
drug from the dosage form.
Preparation of Doxofylline Sustained Release
Tablets:
Doxofylline SR Tablets were prepared by Direct
Compressionmethod.CompositionofeachTabletwas
shown in Table 2. All ingredients were collected and
weighed accurately and passed through sieve no 60.
They were mixed uniformly in a polybag or triturate
for 15 minutes. magnesium stearate was added and
then again blend for 5-6 minutes, Blend was subjected
to compression by using 8 station rotary tablet
punching machine ( Minipress, RIMEK, Ahmedabad)
using 12 mm circular punches and same hardness
used for required number of tablets. Compressed

202
Kumar Gunda, Kumar
tablets were examined as per official standards and
unofficial tests. Tablets were packaged in well closed
light resistance and moisture proof containers.
Experimental Design:
Experimental design utilized in present
investigation for the optimization of polymer
concentration such as, concentration of HPMC
K100M was taken as X1
and concentration of Chitosan
was taken as X2
. Experimental design was given in
the Table 1. Three levels for the Concentration of
HPMC K100M were selected and coded as -1= 5%,
0=10%, +1=15%. Three levels for the concentration of
Chitosan were selected and coded as -1= 5%, 0=10%,
+1=15%. Formulae for all the experimental batches
were given in Table 2 (A. A. Kharia et al., 2010).
Table 1: Experimental design layout
Formulation Code X1
X2
F1
1 1
F2
1 0
F3
1 -1
F4
0 1
F5
0 0
F6
0 -1
F7
-1 1
F8
-1 0
F9
-1 -1
C1
-0.5 -0.5
C2
+0.5 +0.5
Table 2: Formulae for the preparation of doxofylline sustained release tablets as per experimental design
Name of Ingredients
Quantity of Ingredients per each Tablet (mg)
F1
F2
F3
F4
F5
F6
F7
F8
F9
Doxofylline 400 400 400 400 400 400 400 400 400
Microcrystalline Cellulose pH-102 48 68 88 68 88 108 88 108 128
PVP K30 20 20 20 20 20 20 20 20 20
HPMC K 100M 60 60 60 40 40 40 20 20 20
Chitosan 60 40 20 60 40 20 60 40 20
Magnesium Stearate 6 6 6 6 6 6 6 6 6
Talc 6 6 6 6 6 6 6 6 6
Total Weight 600 600 600 600 600 600 600 600 600
Evaluation of Doxofylline Sustained Release
Tablets:
Hardness
The hardness of the tablets was tested by diametric
compression using a Monsanto Hardness Tester. A
tablet hardness of about 2-4 kg/cm2
is considered
adequate for mechanical stability.
Friability
The friability of the tablets was measured in a roche
friabilator (Camp-bell Electronics, Mumbai). Tablets
of a known weight (W0
) or a sample of 20 tablets are
dedusted in a drum for a fixed time (100 revolutions)
and weighed (W) again. Percentage friability was
calculated from the loss in weight as given in equation
as below. The weight loss should not be more than 1 %
Friability (%) = [(Initial weight- Final weight) /
(Initial weight)] x 100
Content Uniformity
In this test, 20 tablets were randomly selected and
the percent drug content was determined, the tablets
contained not less than 85% or more than 115% of the
labelled drug content can be considered as the test was
passed.
Assay
The drug content in each formulation was
determined by triturating 20 tablets and powder
equivalent to 100 mg was dissolved in 100ml of
phosphate buffer pH 6.8, followed by stirring. The
solution was filtered through a 0.45μ membrane
filter, diluted suitably and the absorbance of resultant
solution was measured spectrophotometrically at 263
nm using phosphate buffer pH 6.8 as blank.

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FABAD J. Pharm. Sci., 42, 3, 199-208, 2017
Thickness
Thickness of the all tablet formulations were
measured using vernier calipers by placing tablet
between two arms of the vernier calipers.
In-vitro Dissolution Study
The In-vitro dissolution study for the Doxofylline
sustained release tablets were carried out in USP
XXIII type-II dissolution test apparatus (Paddle type)
using 900 ml of 0.1 N HCl as dissolution medium for
first two hours followed by phosphate buffer pH 6.8 at
50 rpm and temperature 37±0.5°C. At predetermined
time intervals, 5 ml of the samples were withdrawn by
means of a syringe fitted with a pre-filter, the volume
withdrawn at each interval was replaced with same
quantity of fresh dissolution medium. The resultant
samples were analyzed for the presence of the drug
release by measuring the absorbance at 263 nm
using UV -Visible spectrophotometer after suitable
dilutions. The determinations were performed in
triplicate (n=3).
Kinetic modeling of drug release:
The dissolution profile of all the formulations
was fitted in to zero-order, first-order, Higuchi and
Korsmeyer-peppas models to ascertain the kinetic
modeling of drug release (Higuchi., 1963; Peppas.,
1985).
RESULTS AND DISCUSSION:
Sustained release tablets of Doxofylline were
prepared and optimized by 32
factorial design in
order to select the best combination of different
polymers, HPMC K100M, chitosan and also to
achieve the desired prolong/sustained release of
drug from the dosage form/ Formulation. The two
factorial parameters involved in the development
of formulations are, quantity of HPMC K100M &
chitosan as independent variables (X1
, X2
), and In
vitro dissolution parameters such as t10%
, t50% ,
t75%
&
t90%
as dependent variables.
Totally nine formulations
were prepared using 3 levels of 2 factors and all the
formulations containing 400 mg of Doxofylline were
prepared as a sustained release tablet dosage form
by direct compression technique as per the formulae
given in Table 2.
All the prepared tablets were evaluated for
different post compression parameters, drug content,
mean hardness, friability, mean thickness as per
official methods and results are given in Table 3. The
hardness of tablets was in the range of 4.25±0.15-
4.52±0.4 Kg/cm2
. Weight loss in the friability test
was less than 0.54%. Drug content of prepared tablets
was within acceptance range only. Results for all
Post-compression parameters were tabulated or
summarised in Table 3. In-vitro dissolution studies
were performed for prepared tablets using 0.1 N HCl
for first two hours followed by phosphate buffer pH
6.8 as a dissolution media at 50 rpm and temperature
37±0.5°C. The In-vitro dissolution profiles of tablets
were shown in Fig.1-4 (Kinetic Plots) and the
dissolution parameters were summarised in Table
4. Cumulative % drug release of factorial design
formulations F1
-F9
at 12Hr were found to be in the
range of 85.94-99.535%. From the result it reveals
that the release rate was higher for formulations
containing Low level of HPMCK 15M compared
with other Formulations containing Higher level,
due to High concentration of polymer drug may have
entrapped within a polymer matrix causing a decrease
in rate of drug release. variable concentrations of
chitosan produce modified release properties but
high retardation of drug release also not advisable.
Therefore, required release of drug can be obtained by
manipulating the composition of HPMC K100M and
chitosan.
Fig.1 Comparative Zero Order Plots for F1
-F9
Fig.2 Comparative First Order Plots for F1
-F9

204
Kumar Gunda, Kumar
Fig.3 Comparative Higuchi Plots for F1
-F9
Fig.4 Comparative Korsmeyer-Peppas Plots for F1
-F9
Table 3: Post-compression parameters for the formulations
S.No
Formulation
Code
Hardness
(kg/cm2
)
Thickness (mm) Friability (%) Weight Variation (mg) Drug Content (%)
1 F1
4.45±0.11 3.75±0.15 0.54±0.03 599.0±0.14 98.73±0.46
2 F2
4.35±0.05 3.8±0.13 0.51±0.025 598.90±0.31 98.995±0.52
3 F3
4.25±0.15 3.65±0.12 0.51±0.03 599.15±0.30 98.38±0.32
4 F4
4.5±0.21 3.75±0.15 0.53±0.025 600.09±0.01 99.29±0.41
5 F5
4.42±0.5 3.81±0.14 0.5±0.02 600.80±0.02 99.55±0.35
6 F6
4.31±0.20 3.65±0.26 0.51±0.025 601.05±0.10 98.94±0.36
7 F7
4.52±0.40 3.70±0.14 0.525±0.025 598.95±0.16 99.44±0.36
8 F8
4.43±0.20 3.75±0.16 0.495±0.02 598.85±0.10 99.71±0.32
9 F9
4.30±0.5 3.61±0.15 0,505±0.025 599.10±0.21 99.09±0.41
Table 4: Regression analysis data of 32
factorial design formulations of doxofylline
S.
NO
Formulation
Code
KINETIC PARAMETERS
ZERO ORDER FIRST ORDER HIGUCHI
KORSMEYER-
PEPPAS
a b r a b r a b r a b r
1 F1
8.133 6.661 0.995 2.030 0.064 0.974 8.160 25.069 0.981 1.235 0.608 0.988
2 F2
9.940 7.093 0.993 2.045 0.077 0.972 7.798 26.878 0.985 1.282 0.600 0.991
3 F3
13.259 7.229 0.979 2.019 0.082 0.994 6.048 27.968 0.992 1.325 0.591 0.994
4 F4
9.793 7.373 0.994 2.077 0.090 0.948 8.594 27.914 0.985 1.284 0.612 0.992
5 F5
11.600 7.806 0.992 2.195 0.138 0.872 8.232 29.723 0.989 1.326 0.604 0.994
6 F6
14.919 7.942 0.977 2.140 0.137 0.942 6.482 30.813 0.992 1.365 0.595 0.994
7 F7
21.330 7.140 0.955 2.005 0.102 0.992 0.421 28.483 0.997 1.448 0.513 0.995
8 F8
23.137 7.572 0.951 2.179 0.178 0.938 0.782 30.291 0.996 1.477 0.513 0.994
9 F9
26.457 7.708 0.923 2.108 0.200 0.967 2.533 31.381 0.983 1.507 0.508 0.988
F1
to F9
are factorial formulations, r-correlation coefficient, a-Intercept, b-Slope.
Much variation was observed in the t10%
, t50%,
t75%
and t90%
due to formulation variables. Formulation
F4
containing 40 mg of HPMC K100M, 60 mg of
Chitosan showed promising dissolution parameter
(t10%
= 0.508 h, t50%
= 3.343 h, t75%
= 6.686 h, t90%
=
11.108 h). The difference in burst effect of the initial
time is a result of the difference in the viscosity of the
polymeric mixtures (A. A. Kharia et al., 2010). As
the increase in viscosity results in a corresponding
decrease in the drug release, which might be due to
the result of thicker gel layer formulation (Dortunc B
et al., 1997).
The In -vitro dissolution data of Doxofylline SR
tablet formulations was subjected to goodness of fit
test by linear regression analysis according to zero
order and first order kinetic equations, Higuchi’s and
Korsmeyer-Peppas models to assess the mechanism of
drug release. The results of linear regression analysis
including regression coefficients are summarized in
Table 4 and plots shown in Figs 1-4. It was observed

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FABAD J. Pharm. Sci., 42, 3, 199-208, 2017
from the above that dissolution of all the tablets
followed zero order kinetics (Except F3
, F9
due to
Low concentration of Chitosan) with co-efficient
of determination (R2
) values above 0.923 (0.923-
0.995). The values of r of factorial formulations for
Higuchi’s equation was found to be in the range of
0.981-0.997, which shows that the data fitted well to
Higuchi’s square root of time equation confirming
the release followed diffusion mechanism. Kinetic
data also treated for Peppas equation, the slope (n)
values ranges from 1.235-1.507 that shows Non-
Fickian diffusion mechanism anomalous Super case-
II Transport. Polynomial equations were derived
for t10%,
t50%,
t75%
and t90%
values by backward stepwise
linear regression analysis using PCP Disso software
and Response surface plots were constructed using
SIGMAPLOT V13 software. The Response surface
plots were shown in Fig.5-8 for t10%,
t50%,
t75%
and t90%
using X1
and X2
on both the axes respectively. The
dissolution data (Kinetic parameters) of factorial
formulations F1
to F9
were shown in Table 5.
Table 5: Dissolution parameters of doxofylline sustained release tablets 3² full factorial design batches
S.NO
FORMULATION
CODE
KINETIC PARAMETERS
t10% (Hrs)
t50% (Hrs)
t75% (Hrs)
t90% (Hrs)
1 F1
0.719 4.728 9.455 15.710
2 F2
0.591 3.886 7.771 12.912
3 F3
0.561 3.690 7.380 12.262
4 F4
0.508 3.343 6.686 11.108
5 F5
0.331 2.180 4.360 7.244
6 F6
0.334 2.197 4.394 7.301
7 F7
0.448 2.946 5.892 9.789
8 F8
0.258 1.695 3.390 5.632
9 F9
0.228 1.502 3.004 4.991
Fig.5 Response surface plots for t10%
Table 6: Dissolution parameters for predicted and observed values for check point formulations
FORMULATION CODE PREDICTED VALUE ACTUAL OBSERVED VALUE
t10% (h)
t50% (h)
t75% (h)
) t90% (h)
t10% (h)
t50% (h)
t75% (h)
) t90% (h)
C1
0.352 2.312 4.624 7.683 0.355 2.324 4.659 7.689
C2
0.600 3.943 7.886 13.105 0.628 3.957 7.892 13.113

206
Kumar Gunda, Kumar
Fig.9 Comparative dissolution profiles for F4 and Doxolin
Polynomial equation for 3² full factorial designs is
given in Equation
Y= b0
+b1
X1
+b2
X2
+b12
X1
X2
+b11
X1
²+b22
X2
²…
Where, Y is dependent variable, b0
arithmetic
mean response of nine batches, and b1
estimated co-
efficient for factor X1
. The main effects (X1
and X2
)
represent the average result of changing one factor at
a time from its low to high value. The interaction term
(X1
X2
) shows how the response changes when two
factors are simultaneously changed. The polynomial
terms (X1
² and X2
²) are included to investigate non-
linearity. Validity of derived equations was verified
by preparing Two Check point Formulations of
Intermediate concentration(C1
, C2
).
The equations for t10%
, t50%
t75%
and t90%
developed
as follows,
Y1
= 0.442+0.156X1
+0.092X2
-0.016X1
X2
+0.077
X1
2
+0.073X2
2
(for t10%
)
Y2
= 2.907+1.027X1
+0.605X2
-0.102 X1
X2
+0.501
X1
2
+0.481 X2
2
(for t50%
)
Y3
= 5.815+2.053X1
+1.209X2
-0.203 X1
X2
+1.0 X1
2
-
0.962 X2
2
(for t75%
)
Y4
= 9.661+3.412X1
+2.01X2
-0.338 X1
X2
+1.67
X1
2
+1.598 X2
2
(for t90%
)
The positive sign for co-efficient of X1
in Y1,
Y2,
Y3
and Y4
equations indicates that, as the concentration
of HPMC K100M increases, t10%,
t50%,
t75%
and t90%
value
increases. In other words the data demonstrate that
both X1
(amount of HPMC K100M) and X2
(amount
of Chitosan) affect the time required for drug release
(t10%,
t50%,
t75%
and t90%
). From the results of dissolution
rate study it can be concluded that increase in the
amount of the polymer leads to decrease in release
rate of the drug and drug release pattern may be
changed by appropriate selection of the X1
and X2
levels. The Dissolution parameters for predicted from
the polynomial equations derived and those actual
observed from experimental results are summarised
in Table 6. The closeness of Predicted and Observed
values for t10%,
t50%,
t75%
and t90%
indicates validity
of derived equations for dependent variables. The
response surface plots were presented to show the
effects of X1
and X2
on t10%,
t50%,
t75%
and t90%.
The final
best (Optimised) formulation (F4
) is compared with
marketed product (DOXOLIN) shows similarity
factor (f2
) 64.501, difference factor (f1
) 6.862 (There
is no significant difference in drug release because
tcal
is<0.05) Comparative dissolution profile for best
formulation and marketed product shown in fig 9.

207
FABAD J. Pharm. Sci., 42, 3, 199-208, 2017
CONCLUSION
The present research work envisages the
applicability of Polymers such as HPMC K100M and
Chitosan in the design and development of sustained
release tablet formulations of Doxofylline utilizing
the 32
factorial design. From the results of In vitro
dissolution studies it was clearly understand that as
the retardant (HPMC) concentration increases the
release rate of drug was retarded and both of these
polymers can be used in combination since do not
interact with the drug which may be more helpful in
achieving the desired sustained release of the drug for
longer periods. The optimized formulation followed
Higuchi’s kinetics while the drug release mechanism
was found to be Non-Fickian Diffusion, Zero order
release type, controlled by diffusion through the
swollen matrix. On the basis of evaluation parameters,
the optimized formulation F4
may be used once a day
administration in the management of Asthma, COPD
and to reduce the risk of Respiratory Problems. This
may improve the patient compliance by reducing the
dosing frequency. which will ultimately improve the
therapeutic outcome. We could be able to minimize
the per oral cost of the Formulation.
ACKNOWLEDGEMENTS:
The author would like to thank the Principal,
Management & Staff of Narasaraopeta Institute of
Pharmaceutical Sciences, Narasaraopet, Guntur
(D.t), A.P., India for providing support for successful
completion of research work.
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ABBREVATIONS AND SYMBOLS USED
SR - Sustained Release
HPMC - Hydroxy Methyl Propyl Cellulose
BCS - Biopharmaceutical Classification System
Kg - Kilo Gram
Cm - Centi Meter
% - Percentage
mg - milli gram
ml - milli litre
%CDR - Percentage Cumulative Drug Release
UR - Un Released
Min - Minute
ºC - Degree Centigrade
mm - milli meter
t1/2
- Half Life
t10%
- Time taken to release 10% drug from dosage form
t50%
t75%
t90%

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