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SUSTAINED RELEASE MATRIX TABLET OF DILTIAZEM HYDROCHLORIDE IT'S

FORMULATION AND EVALUATION

Data · February 2012

DOI: 10.13140/2.1.3250.4968

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IJAPR Research Paper

Available Online through ISSN: 2230 – 7583
www.ijapronline.org

SUSTAINED RELEASE MATRIX TABLET OF DILTIAZEM

HYDROCHLORIDE IT’S FORMULATION AND EVALUATION

Archana. D. Kajale*, Jayesh M. Wankhade, B. V. Bakde, M. A. Channawar

Department of Pharmaceutics P. Wadhwani College of Pharmacy,

Yavatmal (M.S).INDIA 445001
Received on 17 – 11 - 2011 Revised on 22 – 12- 2011 Accepted on 28 – 01 – 2012

ABSTRACT
Controlled release and sustained release drug delivery has become the standards in the modern pharmaceutical
design and intensive research for achieving better drug product effectiveness, reliability and safety. Oral sustained
release drug delivery (OSRDD) medication will continue to account for the largest share (up to 80%) of drug
delivery systems. The matrix tablet preparation appears to be most attractive approach for the process development
and scale-up point of view. Sustained release systems include any drug delivery system that "achieves slow release
of drug over an extended period of time". If sustain release system is successful in maintaining constant drug levels
in the target tissue or cells, it is considered a controlled release system. A calcium channel blocker, Diltiazem
hydrochloride has found its applicability in cardiovascular diseases advised to take the long term treatment of
cardiovascular medicaments like anti-anginals, anti-hypertensives, etc. The calcium channel blockers are utilized as
the potential agents for the treatment of these diseases. They are considered as a slow calcium channel blockers. The
direct compression method was adopted for the preparation of sustained release matrix tablets with the 10mm
punches and targeted weight of 350mg. Hypromellose is primarily used as a tablet binder, in film-coating, and as a
matrix for use in extended-release tablet formulations. The results revealed that formulations with the drug polymer
ratio 1.0:0.5 (F1, F4 and F7) showed higher drug release rates in the range of 94.74 to 90.72% when compared
1.0:1.0 ratio (F2, F5 and F8) which showed a drug release rates from 93.69 to 88.92% and those of 1.0:1.5 ratio (F3,
F6 and F9) which have displayed drug release rates in the range of 92.64 to 86.62 %over a period of 12 hours. This
indicates that as the polymer concentration increased, the drug release rate was found to be retarded.
Key Words: Calcium channel blocker, Diltiazem hydrochloride, Matrix tablet, Sustain release, Control release.

INTRODUCTION
An ideal dosage regimen in the drug therapy of any
disease is the one which immediately attains the
desired therapeutic concentration of drug in plasma
(or at site of action) and maintains it constant for the
entire duration of treatment. This is possible through
administration of a conventional dosage form in a
particular dose and at a particular frequency. The
frequency of administration or the dosing interval of
any drug depends upon its half-life or mean residence
time and its therapeutic index.1
Address for correspondence:-
Archana D. Kajale
“Arunoday”, 18, Radha Nagri,
Wadgaon Road, Yavatmal. Pin coad- 445001.
archana.kajale@gmail.com,
Phone: +919423133066
Recently, controlled release and sustained release
drug delivery has become the standards in the
modern pharmaceutical design and intensive research
for achieving better drug product effectiveness,
reliability and safety. Oral Sustained Release Drug
Delivery (OSRDD) medication will continue to
account for the largest share (up to 80%) of drug
delivery systems2. The matrix tablet preparation
appears to be most attractive approach for the process
development and scale-up point of view. 3
An appropriately designed sustained-release drug
delivery system can be a major advance towards
solving these two problems. It is for this reason that
the science and technology responsible for
development of sustained release pharmaceuticals
have been and continue to be the focus of a great deal

IJAPR / Feb. 2012/ Vol. 3 / Issue. 2 / 753 - 761 753

 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research
of attention in both industrial and academic
laboratories.
Sustained release systems include any drug delivery
system that "achieves slow release of drug over an
extended period of time". If the system can provide
some control, whether this is of a temporal or spatial
nature, in other words, if the system is successful in
maintaining constant drug levels in the target tissue
or cells, it is considered a controlled release system.
If it is unsuccessful at this, nevertheless extends the
duration of action over that achieved by conventional
delivery. It is considered a prolonged-released
system.4
The increased risk of cardiovascular diseases advised
to take the long term treatment of cardiovascular
medicaments like anti-anginals, anti-hypertensives,
etc. The calcium channel blockers are utilized as the
potential agents for the treatment of these diseases.
They are considered as a slow calcium channel
blockers. 5
A calcium channel blocker, Diltiazem hydrochloride
has found its applicability in such a life threatening
cardiovascular diseases and widely used as an anti-
anginal, anti-hypertensive and an anti-arrhythmic
agent. It is a BCS class I (highly soluble, highly
permeable) drug with extensive and highly variable
hepatic first pass metabolism following oral
administration, with systemic bioavailability of
between 36-50% and half life of 3.5  1.2 hours.
When such a drug administered in conventional
immediate release dosage form, the frequency of
administration increased up to 3-4 times in day due to
its shorter half-life. 6
In such a case, the sustained release formulation will
be beneficial than the immediate release dosage form
as therapeutic level is maintained for an extended
period of time, eliminating maxima in drug
concentration commonly associated with multiple
doses.
In the past many sustained release systems for low or
sparingly soluble drugs have been developed, but
considerable difficulties have been experience in the
formulation of freely soluble (class I) drugs.
Suppressing the diffusion of embedded drug possess
major challenges due to inherent solubility of drug.
Hypromellose is primarily used as a tablet binder, in
film-coating, and as a matrix for use in extended-
release tablet formulations. Concentrations between
2% and 5% w/w may be used as a binder in either
wet- or dry-granulation processes. High-viscosity
grades may be used to retard the release of drugs
from a matrix at levels of 10–80% w/w in tablets and
capsules.7
MATERIAL AND METHODS
Material
IJAPR / Feb. 2012/ Vol. 3 / Issue. 2 / 753 - 761
Diltiazem Hydrochloride was provided by Themis
Laboratories Ltd., Mumbai. Hypromellose K4M,
K15M and K100M, cyclocel (ph102) was provided
by Weiming Pharmaceuticals, Taiwan.
METHOD
Formulation of core batches
Various batches (Table no1) of tablets were prepared
by combining varying percentages of hypromellose
K4M, K15M, K100M with Different tablet
formulations were prepared by by taking various
viscosity grades of hypromellose, i.e. K4M, K15M and
K100M. All the agents were added in various
concentrations of drug to polymer ratio viz., 1.0:0.5,
1.0:1.0 and 1.0:1.5. by direct compression method.
All the ingredients were passed through 90µm sieve.
The ingredients were accurately weighed and mixed
together in a glass mortor for 10 minutes. Finally the
magnesium stearate was added and mixed for
additional 2 minutes. The lubricated powder blend
was then compressed using 10mm standard flat faced
punch on a 10 station tablet punching machine. The
total tablet weight was set at 350mg. The
compression pressure was adjusted during tableting
of each formula to get tablet hardness in the range of
5 to 7 kg/cm3.
EVALUATION OF BATCHES
Pre formulation testing: Pre formulation Testing of
powder blends all the batches were performed like
Bulk Density, Tapped Density, Hausner’s ratio,
Angele of repose, Compressibility Index shown in
Table no 2.
Formulation testing: (8-11)
In this Hardness, Thickness, Weight variation,
Friability, Drug Content Uniformity tests were
performed using 10 tablets of each batch shown in
Table no 3.
In-vitro Release Profile Study of Formulated
Tablets 12-13
Method
In vitro drug release studies were carried out
using USP 25 (Type II) apparatus in 900ml of
dissolution medium (n=3) maintained at 37±1 0C at a
speed of 100 rpm. Distilled water was used as
dissolution medium to avoid the effects of pH change
on the solubility of diltiazem hydrochloride as it
decreases with the increasing pH. Aliquots of 10ml
were withdrawn at predetermined time intervals
using calibrated pipette during a 12 hours period and
filtered. An equivalent amount of fresh dissolution
medium, maintained at 37±10C was added after
withdrawing each sample to maintain the sink
conditions. The drug concentrations in the sample
analyzed spectrophotometrically (double beam UV,
Thermo) at 237nm. The mean of three readings was
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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research
used to determine concentration. (Table no.4, Fig
no.1-3)
Drug Kinetic Study:14
The release data obtained from various batches were
studied with respect to the effect of drug: polymer
ratio, diluents ratio. To analyze the mechanism of drug
release from the formulation, the dissolution profile of
optimized batches was fitted to zero-order, first-order,
Higuchi, Hixson-Crowell, Korsemeyer and Peppas to
ascertain the kinetic modeling of drug release as
shown in (Table no 5).
Water uptake and erosion studies: 15,16
The selected formulations were subjected to the
swelling and erosion studies. The results of the
swelling studies were shown in Table No. 6 and 7
and Fig No. 4 and 5.Swelling of the tablet excipients
particles involves absorption of water resulting in an
increase in weight and volume. Water uptake by the
particle may be due to saturation of capillary spaces
within the particles or hydration of macromolecules.
The water enters the particles through pores and bind
to large molecules breaking the hydrogen bond and
swelling of the particle. Three tablets were used per
time point. At predetermined time intervals, tablets
were removed from the medium and lightly patted
using tissue paper to remove excess surface water.
The wet weight of tablets was determined and then
dried at 700C until constant weight was achieved
before reweighing to determine dry weight.
The following equations were used to determine
percent weight gain (water uptake) and percent mass
loss:
Weight gain (%) =
Wet Weight - Dry Weight
 100
Dry Weight
Mass loss (%) =
Original Weight - Remaining (Dry) Weight
 100
Original Weight
FT-IR SPECTROSCOPY
It’s important to check any kind of interaction
between drug candidate and polymer. The polymers
which are to be incorporated into formulation should
be compatible with the drug. This compatibility
study or interaction study was done using Fourier
transformed infrared spectroscopy. IR spectra of pure
diltiazem hydrochloride and polymers viz.
hypromellose (K4M, K15M, and K100M), were
taken separately. Then to know if there is any
interaction between drug and polymer, IR spectra of
diltiazem hydrochloride and other polymers were
taken in combination. (Fig no 6, Table no 8.)
Accelerated Stability Studies
IJAPR / Feb. 2012/ Vol. 3 / Issue. 2 / 753 - 761
The tablets from the selected and optimized batch
(H2X2) were studied for stability and kept under the
accelerated conditions of temperature and moisture
(humidity) for the period of three months. The tablets
were studied for stability at 40°C and 75% RH
conditions for the period of three months. Each tablet
was individually weighed and wrapped in an
aluminum foil and packed in black PVC bottle and
put at above specified conditioned in a heating
humidity chamber for 3 months. After each month
the, the formulation was observed for changes in
physical appearance and analyzed for in-vitro drug
release. The results were illustrated in (Table No.9
and Fig. No.7).
RESULTS AND DISCUSSION
In the present study, an attempt has been made to
prepare sustained release matrix tablet. Diltiazem
hydrochloride was chosen as a model drug due to its
low oral bioavailability, short half-life, water
solubility and multiple daily dosing, which makes it
an appropriate candidate for a formulation in a
sustained release, twice-a-day dosage form.
The screening of various grades of hypromellose
(K4M, K15M, K100M) was carried out in 1:1, 1:1.5,
1:2 drug to polymer ratio and nine batches were
prepared. The batch F3 (92.64% drug release),
containing hypromellose K4M in 1:1.5 ratio were
selected as per USP criteria for drug release of
diltiazem hydrochloride labeled for 12 hours dosing.
The characterization of drug sample by physical and
analytical methodologies revealed that the received
drug sample was as per pharmacopoeial standard.
Further, the drug and other polymers were subjected
to interaction studies by FTIR spectroscopy. No
interactions were found between drug and polymer
samples.
The powder blend was evaluated for physical
properties like bulk density, tapped density,
compressibility index, Hausner ratio and angle of
repose which shown the results within prescribed
compendial limits.
The direct compression method was adopted for the
preparation of sustained release matrix tablets with
the 10mm punches and targeted weight of 350mg.
All the formulations were subjected to in-vitro
dissolution studies. The results revealed that
formulations with the drug polymer ratio 1.0:0.5 (F1,
F4 and F7) showed higher drug release rates in the
range of 94.74 to 90.72% when compared 1.0:1.0
ratio (F2, F5 and F8) which showed a drug release
rates from 93.69 to 88.92% and those of 1.0:1.5 ratio
(F3, F6 and F9) which have displayed drug release
rates in the range of 92.64 to 86.62 %over a period of
12 hours. This indicates that as the polymer
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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research

concentration increased, the drug release rate was
found to be retarded.
As formulation F3 containing hypromellose K4M
shown 92.64% cumulative drug release pattern,
which was according to the Acceptance Table of
Test 2 given in USP-NF 2007 for the 12 hours dosing
of diltiazem hydrochloride, this batch was chosen for
the further studies in the ratio of 1.0:1.5 (Drug:
Polymer).
Most of the formulations prepared were found to
release by the drug by non-fickian transport
(anomalous) since the release exponent values (n)
were found to be in the range of 0.701 to 0.936.
Although the drug release fitted better into an
anomalous/non-fickian diffusion mechanism, a model
representing zero order was also very close (‘r’
values form 0.986 to 0.992). The ‘r’ values for the
Higuchi plots were found to be in the range of 0.954
to 0.981 which confirms diffusion controlled drug
release from all the prepared matrices.
CONCLUSION
As the concentration of polymer increases there is
decrease of drug release. The overall frequency of
administration of a drug candidate like Diltiazem HCl
was successfully reduced to 2 times a day, which
generally requires dosing in 3 to 4 times a day in
conventional tablet dosage form. The improved
patient convenience might thus be obtained by the
administration of such a dosage form with minimal
blood level fluctuations. The release retardant
materials are cheap, readily available, safe, having
wide regulatory acceptance and easy to handle for
economic point of view. It may beneficial to adopt
such simple technology for the commercial
production of sustained release matrix tablets.

TABLES AND FIGURES

Table No. 1: FORMULATION OF CORE BATCHES
(Composition of Diltiazem HCl matrix tablet in milligrams)
HPMC HPMC HPMC
Formulations DHZ Cyclocel® Total
K4M K 15M K100M

F1 90.0 45.0 ------- ---------- 211.5 350

F2 90.0 90.0 ------- ---------- 166.5 350
F3 90.0 135.0 ------- ---------- 121.5 350
F4 90.0 ------- 45.0 ---------- 211.5 350
F5 90.0 ------- 90.0 ---------- 166.5 350
F6 90.0 ------- 135.0 ---------- 121.5 350
F7 90.0 ------- ------- 45.0 211.5 350
F8 90.0 ------- ------- 90.0 166.5 350
F9 90.0 ------- ------- 135.0 121.5 35
(Magnesium Stearate was added in 1.0% concentration.)

Table No. 2: Evaluation of Physical Properties of Powder Blend ( pre formulation testing )
Bulk Tapped Angle of
Compressibility Hausner
Formulation Density Density Repose
(%) Ratio
(g/cm3) (g/cm3) (θ)
F1 0.478 0.522 8.42 1.09 260-15’
F2 0.502 0.554 9.39 1.10 270 -20’
F3 0.486 0.526 7.61 1.08 250-12’
F4 0.430 0.508 15.35 1.18 310-20’
F5 0.482 0.528 8.71 1.1 260-06’
F6 0.465 0.516 9.88 1.11 320-24’
F7 0.442 0.502 11.95 1.14 300-15’
F8 0.436 0.496 12.1 1.14 350-22’
F9 0.424 0.468 9.40 1.10 280-18’

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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research

Table No.3: Tablet Evaluation Tests for Formulation

Hardness Friability Thickness Content Weight
Formulation Uniformity Variation
(Kg/cm2) (%) (mm) (%) Test (mg)
F1 5.5 ± 0.34 0.69 ± 0.09 3.3 ± 0.08 100.02 352.25
F2 6.0 ± 0.32 0.52 ± 0.12 3.2 ± 0.10 95.62 349.50
F3 6.5 ± 0.28 0.50 ± 0.08 3.3 ± 0.22 98.34 350.62
F4 5.0 ± 0.36 0.67 ± 0.16 3.3 ± 0.24 96.48 348.84
F5 5.8 ± 0.40 0.65 ± 0.14 3.2 ± 0.09 92.22 350.42
F6 6.2 ± 0.30 0.54 ± 0.10 3.1 ± 0.26 99.02 351.60
F 6.6 ± 0.35 0.59 ± 0.15 3.1 ± 0.20 91.65 348.82
F8 6.0 ± 0.34 0.53 ± 0.12 3.2 ± 0.08 95.40 349.66
F9 6.4 ± 0.29 0.58 ± 0.16 3.2 ± 0.14 97.12 352.92

Table No. 4: In-vitro Release Profile Study of Formulated Tablets

Cumulative Percent Drug Released
Formulation Code
Time F1 F2 F3 F4 F5 F6 F7 F8 F9
1 23.62 20.94 18.44 20.57 18.89 16.07 19.27 16.72 15.92
2 29.92 25.71 23.89 26.89 24.29 20.87 25.83 21.36 19.03
3 34.59 30.34 27.22 31.72 28.76 26.56 28.67 26.47 23.42
4 39.35 37.24 38.37 35.45 36.12 35.37 36.18 30.18 30.87
5 49.58 43.61 41.36 40.37 41.47 38.58 41.94 37.59 41.25
6 56.61 54.81 45.15 47.72 46.67 42.67 46.09 45.29 45.69
7 61.89 59.45 52.06 56.64 54.42 51.92 52.31 58.61 50.18
8 68.75 66.56 63.17 65.53 66.37 63.18 62.46 63.96 64.56
9 78.26 77.27 72.82 79.83 77.07 76.25 76.52 71.85 72.35
10 87.56 85.06 81.32 83.02 83.27 78.74 84.75 82.56 80.46
11 92.85 89.78 87.24 88.51 86.71 83.67 87.04 85.64 83.74
12 94.74 93.69 92.64 93.17 90.62 86.95 90.72 88.92 86.62

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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research

In-vitro Drug Release Studies of Formulations F1 to F3

100
90
80

% Drug Released
70
60
50
40
30 F1

20 F2
10 F3

0
0 5 10 15
Time (Hours)

Fig. No.1, In-Vitro dissolution studies of formulation F1 to F3

In-vitro Drug Re le as e Studie s of Form ulations F4 to F6

100
90
80
% Drug Released

70
60
50
40
F4
30
F5
20
F6
10
0
0 5 10 15
Time (Hours)

Fig. No. 2, In-Vitro dissolution studies of formulation F4 to F6

In-vitro Drug Release Study of Formulations F7 to F9

100
90
80
%Drug Released

70
60
50
40 F7
30
F8
20
F9
10
0
0 5 10 15
Time (Hours)

Fig. No. 3 In-Vitro dissolution studies of formulation F7 to F9

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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research

Table No. 5 : Drug Release Kinetic Studies from Formulation

Formulation n Zero-order First-order Higuchi
F1 0.701 0.986 0.919 0.972
F2 0.774 0.992 0.922 0.973
F3 0.837 0.995 0.896 0.953
F4 0.751 0.991 0.901 0.956
F5 0.814 0.992 0.938 0.974
F6 0.887 0.992 0.950 0.978
F7 0.819 0.989 0.913 0.954
F8 0.887 0.991 0.935 0.967
F9 0.936 0.993 0.957 0.981
Table No. 6: % Water Uptake Studies

Time (Hours) % Water Uptake

X G H H2X2 H2G2 H2C2
0 0 0 0 0 0 0
2 172.28 136.54 110.6 125.1 135.22 86.29
4 248.62 214.55 205.3 185.3 186.39 165.63
6 359.29 295.62 284.3 283.6 285.52 205.79
8 414.64 378.34 344.18 372.62 353.78 293.55
10 475.94 445.76 410.58 415.05 446.14 386.56
12 541.61 532.92 469.84 489.19 524.58 425.68
% Water Uptake Studies of Selected Formulations

600

500
% Water Uptake

400

300 X
G
200 H
H 2X2
100 H 2G2
H 2C 2
0
0 5 10 15
Time (Hours)

Fig. No. 4: % Water uptake studies of selected formulations.

Table No. 7: % Mass Loss Studies

% Mass Loss
Time (Hours)
X G H H2X2 H2G2 H2C2
1 15.26 11.38 10.68 12.57 12.74 14.87
2 22.63 16.56 13.74 14.68 15.23 16.37
4 34.74 19.67 20.18 22.8 21.83 23.48
6 52.06 27.08 30.98 33.48 35.18 36.38
8 57.32 36.18 43.36 45.18 47.58 49.18
10 74.22 53.84 51.93 54.96 60.97 62.07
12 80.93 60.34 57.48 59.38 64.86 70.76

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 Archana. D. Kajale., et al. / International Journal of Advances in Pharmaceutical Research

% Ma ss Loss Studie s of Se le cte d Formula tions

90

80

70

60

% Mass Loss
50

40 X
G
30 H
H 2X2
20
H 2G2
10 H 2C 2

0
0 2 4 6 8 10 12 14
Time (Hours)

Fig. No. 5: % Mass loss studies of selected formulations.

60

%T

50

40

30

665.40

536.17
761.83
2734.87

821.62
1137.92

864.05
2837.09

20

480.24
1110.92
3033.82
3053.11

2927.74

910.34
3002.96

2939.31

1159.14
2964.39

1317.29

837.05
1373.22

1010.63
1083.92

973.99

779.19
10

1606.59

1292.22
1581.52

1180.35
1413.72
1446.51
1473.51

1026.06
2542.00

1510.16

1240.14
2501.50

1058.85
1743.53
2455.21

1255.57
1677.95

1217.00
2335.64
2358.78

-10

3600 3200 2800 2400 2000 180 0 1600 1400 1200 1000 800 600
D R U G 13 1/c m

Fig No. 6: FTIR of Diltiazem Hydrochloride

Table No. 8: Interpretation of studied FTIR peaks with their Characteristics functional groups.
Peaks (cm-1) Characteristic Functional Groups
1700-1650 -CO str
1750 Esteric –CO str
3350-3200 -NH str
3000-2900 Aliphatic (CH3,CH2,CH) str
3100-3000 Aromatic CH str

Table No. 9: Effect of temperature and humidity on in-vitro drug release

Time
% Drug Released
(Hours)
0 Month 1 Month 2 Months 3 Months
2 23.68 23.16 24.06 24.92
4 37.14 36.75 37.28 37.75
6 56.68 56.64 57.14 58.42
8 76.12 76.32 76.74 77.96
10 88.34 87.26 87.65 88.32
12 92.78 91.48 92.08 92.46

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Accelerated Stability Study (% Drug Released)

100
90
80

% Drug Released
70
60
50
40 0 M onth
1 M onth
30
2 M onths
20
3 M onths
10
0
0 5 10 15
Time (Hours)

Fig. No. 7: % Drug release study of optimized formulation at accelerated Conditions

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