DESIGN, DEVELOPMENT OF FORMULATION OF EPERISONE

HYDROCHRODIDE FLOATING SUSTAIN REALEASE TABLET AND

ITS EVALUATION.

Dr. Kavita Shukla Verma1, Anjali Agrwal2, Deepak patel3, Abhitav Tiwari*4

1
Principal, Shri Ram institute of pharmacy Jabalpur Madhya Pradesh.482002.

2
Post Graduate Student, Shri Ram institute of pharmacy Jabalpur Madhya
Pradesh.482002.

3
Assistant Professor Shri Ram institute of pharmacy Jabalpur Madhya
Pradesh.482002.

4
Research Scholar, Guru Ghasidas University, Bilaspur Chhattisgarh.495009.

Corresponding Author:

Abhitav tiwari

Research Scholar, Guru Ghasidas University, Bilaspur Chhattisgarh.495009

[email protected]

Abstract
The aim of this research was, by employing hydroxy-propyl-methylic cellulose (HPMC K15,
HPMC K5) and PVP K30as matrix creation polymer, to design and assess orally extended-
dump floating matrix tablets for the eperisone HCl method of direct compression. As a gas
producing agent, sodium bicarbonate and citric acid were used, with the increasing challenges
and costs of marketing innovative pharmaceuticals, more focus has been dedicated to the
development of sustained release (SR) or controlled release (CR) systems. Long-term, constant
and reproducible activity, decreased dosage and toxicity requests, better therapy and more
patient compliance can be achieved using extended release or controlled release systems. The
sort and percentage of polymers used in the preparation are the most important factors to
consider. Eperisone hydrochloride is a centrally acting throat relaxant. The FTIR spectra of
the eperisone HCl and other excipients alone and in combination show the
compatibility of the drug and excipients. Nine formulations of different polymer
percentages were formulated (F1-F9).Pre-compression parameters were evaluated. The
influence of matrix forming agents and binary mixtures of them on eperisone HCl release was
investigated. The formulated tablets were characterized by thickness and diameter, drug
content, hardness, friability, uniformity of weight, Invitro buoyancy studies and
dissolution rate studies. Prepared optimized formulation (F7) showed the release of drug form
gastroretentive formulation 99.45% after 12 hrs. When the regression coefficient values of
were compared, it was observed that ‘r2’ values of korsmeyer peppas was maximum i.e. 0.988
hence indicating drug release from formulations was found to follow korsmeyer peppas release
kinetics. Eperisone HCl floating tablets exhibited increased gastric residence time, there by
improved bioavailability and therapeutic effect of the drug.

Keywords: Sustained release, Eperisone hydrochloride, Direct

INTRODUCTION
Sustained release (SR) has given a new breakthrough for novel drug delivery system in the
field of Pharmaceutical technology. Sustained release constitutes any dosage form that
provides medication over an extended time or denotes that the system is able to provide some
actual therapeutic control whether this is of a temporal nature, spatial nature or both.
Sustained release system generally do not attain zero order type release and usually try to
mimic zero order release by providing drug in a slow first order[1]. Repeat action tablet are an
alternative method of sustained release in which multiple doses of drug are an alternative
method of sustained release, in which, multiple doses are contained within a dosage form and
each dose is released at a periodic interval[2].
Sustained release (SR) preparations are not new but several new modifications are being
introduced. They are also referred to as “long acting” or “delayed release” when compared to
“rapid” or “conventional” release preparations. The term sometimes overlaps with “controlled
release,” which implies more sophisticated control of release and not just confined to the time
dimension[3]. Sustained release has many advantages such as the frequency of drug
administration is reduced, patient compliance can be improved, drug administration can be
made more convenient as well, the blood level oscillation characteristic of multiple dosing of
conventional, etc,[4]. Eperisone hydrochloride which is chemically known as 4’-ethyl-2-
methyl-3-piperidino propiophenone hydrochloride, has chemical formula C17H25NO and
belongs to the class of muscular relaxants, having molar mass 259.387g/mol9. The drug
acts by acting on central nervous stem cells providing relaxation of both skeletal and
vascular smooth muscles. Oral eperisone is effectively used three times daily (t.i.d) at
dosage regimen of 100 mg[5]. It is well known for use in the treatment of muscular
spasm, lower back pain, cervical spondolysis and in spastic paralysis in
terms of cerebrovascular disease. The drug is well tolerated at doses of with mild GI
symptoms involving nausea; abdominal cramps, headache and dizziness are the
commonly observed adverse effects10-12. The drug is rapid absorption after oral
administration. It has biological half-life of about 1-4.3 hour, its rapid elimination rules
out risk of accumulation[6].

MATERIAL AND METHODS

Material

Eperisone hydrochloride was a gift sample from pharmaceutical company. Di

potassium Hydrogen Orthophosphate, PVP & Sodium Chloridewere purchased from
S. D. Fine Chem. Ltd., Mumbai. Methanol, Ethanol, Chloroform & Citric acid were
purchased from Qualigens Fine Chemicals, Mumbai. HPMC was purchased from
Ozone international, Mumbai. Sodium bicarbonate was purchased from Chem pure
Pvt. Ltd. Magnesium stearate was purchased from Jiangsu Huaxi International. Talc
& Lactose was purchased from Loba Chemie Pvt. Ltd. Double distilled water was
prepared freshly and used whenever required. All the chemicals used in this work
were of analytical grade.

Methods

Preformulation studies

Organoleptic properties:

Organoleptic properties of the drug substance are very important for designing the
dosage form. The colour, odour and tests of the drug are characterized[7].

Solubility Analysis:
For the determination of solubility of Eperisone HCl in various solvents that were
methanol, ethanol, chloroform and distilled water etc. 5mg of Eperisone HCl was
added to 10 ml of each solvent in a test tube and shaken for few minutes at room
temperature (21.0 ± 1.5°C)[8].

Loss on drying (%)

.Loss on drying is directly measured by IR moisture balance. Firstly calibrated the

instrument by knob, then taken 5 gram of sample (powder) and fixed the
temperature at 100°C to 105°C for 15 minutes and constant reading, and fixed the
knob and check percent moisture[9].

Melting point

Melting point of Eperisone HCl was determined using open capillary method by
melting point apparatus. Fine powder of the drug was filled in glass capillary tube
which was sealed at one end. The capillary tube was tied to the thermometer and
thermometer was kept in theils tube apparatus and then slowly increased the
temperature of the apparatus and recorded the temperature at which drug was
completely melted. The observed melting point of the drug was compared with
melting point given in literature[10].

Moisture Content Determination

Principle:
The titrimetric determination of water is based upon the quantitative reaction of
water with an anhydrous solution of sulphur dioxide and iodine in the presence of a
buffer that reacts with hydrogen ions. In the original titrimetric solution, known as
Karl Fisher Reagents, the sulfur dioxide and iodine was dissolved in pyridine and
methanol. The test specimen may be titrated with the reagent directly, or the analysis
may be carried out by a residual titration procedure[11].
B. R X F
% Water= x 100
Wt

Where,
B.R = volume of Karl Fischer reagent consumed in ml.
F= Karl Fischer reagent factor in mg/ml.
Wt= weight of sample taken in g.

Determination of UV-visible absorption maxima of Eperisone HCl

Preparation of standard solutions

A standard stock solution of Eperisone HCl was prepared by dissolving 10 mg

(accurately weighed) of the standard Eperisone HCl in 10 ml of 0.1 N HCl. This
stock solution was further diluted to get working standard solutions of 10µg/ml.
Aliquots (0.1, 0.2, 0.3, 0.4, 0.5 ml) of working standard solution were transferred
into a series of 10 ml volumetric flasks to get the desired concentration range for
calibration curve. The volumes were made up with 0.1 N HCl solution[12].

FTIR spectroscopy of Eperisone HCl

The purity of pure drug was determined by I.R. Approximately 10 mg of Eperisone

HCl was triturated with 100 mg of dried potassium bromide (KBr) in agatte mortar.
Pellet was prepared by using KBr press pellet method. Pellet was scanned between
the ranges of 400 to 2000 cm -1 with background correction. The spectrum was
recorded and major peaks were determined[13].

Preparation and characterization of floating tablet

Method for preparation of Eperisone HCl floating tablet

Direct compression was followed to manufacture the gas generating floating tablets
of Eperisone HCl. Nine different formulations (F1, F2, F3, F4, F5, F6, F7, F8, &
F9) were prepared by direct compression 56. All the polymers selected, drug and
excipients were passed through sieve no. 40 before using into formulation. The
amount and ratio of drug and polymers were weighed as per given in table No. 7.1
and all the formulation were used for further evaluations parameters[14].
 Optimization of Gastro retentive floating tablets of Eperisone HCl
Table 1. Various formulations of gastro retentive tablets
Excipients(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9
Eperisone HCl 50 50 50 50 50 50 50 50 50

HPMC K 5 50 75 100  - -  -  25 37.5 50

HPMC K 16 -  - -  50 75 100 25 37.5 50

PVP K30 10 10 10 10 10 10 10 10 10

Citric acid 5 5 5 5 5 5 5 5 5

NaHCO3 10 10 10 10 10 10 10 10 10

Mg(C18H35O2)2 5 5 5 5 5 5 5 5 5

Talc 10 10 10 10 10 10 10 10 10

Lactose 60 35 10 60 35 10 60 35 10

Total Weight 200 200 200 200 200 200 200 200 200

Excipients like Sodium bicarbonate, citric acid anhydrous, Magnesium Stearate

were selected for the study. Sodium bicarbonate and citric acid were used as gas
generating agent. Citric acid was also used as an antioxidant. Steps involved in the
manufacture of tablets, first the drug; polymer and other excipients selected were
passed through 40 mesh sieve. Required quantity of drug, polymer and excipients
were weighed properly and transferred into polyethylene bag and the blend was
mixed for at least 15 min. The blend obtained was then lubricated by adding 1%
magnesium stearate and again mixed for another 5min[15].

Bulk density
Accurately weighed 1gm of powder was poured into the measuring cylinder
carefully level the powder without compacting, if necessary and read the unsettled
apparent volume, Vo, to the nearest graduated unit. Calculate the bulk density in gm
per ml, gm/cc by the formula[16].
Bulk density = Bulk Mass/ Bulk Volume
Tapped density
Accurately weighed 10gm of powder was poured into the measuring cylinder
carefully level the powder and read the tapped volume (after 50-60 times tapping),
Vt to the nearest graduated unit[17]. Calculate the tapped density in gm per ml, gm/
cm3 by the formula:
Tapped density = Bulk Mass/ Tapped Volume

Compressibility index (Carr’s index):

Compressibility index (C.I.) is an important measure that can be obtained from the
bulk and tapped densities. Carr’s index a material having values of less than 20% to
30% is defined as the free flowing material[18].
It can be calculated as per given formula:

Tapped density- Bulk density

C.I. = x100
Tapped density
Hausner ratio
It indicates the flow properties of the powder and is measured by the ratio of tapped
density to bulk density.
Hausner ratio = Tapped density / Bulk Density
Evaluation of tablets
All the tablets were evaluated for following different parameters which includes;

General Appearance
Five tablets from different batches were randomly selected and organoleptic
properties such as color, odor, taste, shape, were evaluated. Appearance was judged
visually. Very good (+++), good (++), fair (+) poor (-), very poor (- -).

Thickness and diameter

Thickness and diameter of tablets were determined using Vernier caliper. Five
tablets from each batch were used, and an average value was calculated[20].

Drug content
Twenty tablets were taken and amount of drug present in each tablet was
determined60. The tablets were crushed in a mortar and the powder equivalent to
100mg of drug was transferred to 100ml standard flask. The powder was dissolved
in 50 ml of 0.1 N HCl and made up to volume with of 0.1 N HCl. The sample was
mixed thoroughly and filtered through a 0.45μ membrane filter. The filtered solution
was diluted suitably and for drug content by UV spectrophotometer at λmax of 272nm
using of 0.1 N HCl as blank[21].
Hardness
For each formulation, the hardness of five tablets was determined using the
Monsanto hardness tester (Cadmach).
Friability
The friability of a sample of 10 tablets was measured using a Friability tester
(Electro Lab). Ten tablets were weighed, rotated at 25 rpm for 4 minutes. Tablets
were reweighed after removal of fines (dedusted) and the percentage of weight loss
was calculated.

Uniformity of weight
Twenty tablets were randomly selected from each batch individually weighed, the
average weight and standard deviation of 20 tablets was calculated.

In vitro buoyancy studies

The tablets were placed separately in a 100 ml glass beaker containing simulated
gastric fluid (SGF), pH 1.2 as per USP. The time required for the tablet to rise to the
surface and float was determined as floating lag time[22].

In vitro dissolution rate studies

In vitro drug release of the sample was carried out using USP- type II dissolution
apparatus (Paddle type) . The dissolution medium, 900 ml 0.1N HCl was placed into
the dissolution flask maintaining the temperature of 37±0.50ºC and rpm of 75. One
Eperisone HCl tablet was placed in each basket of dissolution apparatus. The
apparatus was allowed to run for 10 hours. Sample measuring 5 ml were withdrawn
after every 1 hour up to 12 hours using 10ml pipette. The fresh dissolution medium
(37ºC) was replaced every time with the same quantity of the sample and take the
absorbance at 272 nm using spectroscopy[23].

Mathematical treatment of in-vitro release data

 Zero-order kinetics: The pharmaceutical dosage forms following this profile
release the same amount of drug by unit of time and it is the ideal method of drug
release in order to achieve a pharmacological prolonged action. The following
relation can, in a simple way, express this model:

Qt = Qo + Ko t
Where Qt is the amount of drug dissolved in time t, Qo is the initial amount of drug
in the solution (most times, Qo=0) and Ko is the zero order release constant.

First-order kinetics: The following relation expresses this model:

Where Qt is the amount of drug dissolved in time t, Qo is the initial amount of drug
in the solution and K1 is the zero order release constant.

In this way a graphic of the decimal logarithm of the released amount of drug versus
time will be linear. The pharmaceutical dosage forms following this dissolution
profile, such as those containing water-soluble drugs in porous matrices, release
drug in a way that is proportional to the amount of drug remaining in its interior, in
such way, that the amount of drug released by unit of time diminish.

Higuchi model: Higuchi developed several theoretical models to study the release
of water-soluble and low soluble drugs in semi-solid and/or solid matrixes.
Mathematical expressions were obtained for drug particles dispersed in a uniform
matrix behaving as the diffusion media. The simplified Higuchi model is expressed
as:

Where Q is the amount of drug released in time t and KH is the Higuchi dissolution
constant. Higuchi model describes drug release as a diffusion process based in the
Fick’s law, square root time dependent. This relation can be used to describe the
drug dissolution from several types of modified release pharmaceutical dosage
forms such as transdermal systems and matrix tablets with water-soluble drugs.

Korsmeyer-Peppas model: Korsmeyer et al. used a simple empirical equation to

describe general solute release behaviour from controlled release polymer matrices:
Where Mt/M is fraction of drug released, a is kinetic constant, t is release time and
n is the diffusional exponent for drug release. ’n’ is the slope value of log Mt/M
versus log time curve. Peppas stated that the above equation could adequately
describe the release of solutes from slabs, spheres, cylinders and discs, regardless of
the release mechanism. Peppas used this n value in order to characterize different
release mechanisms, concluding for values for a slab, of n =0.5 for fickian diffusion
and higher values of n, between 0.5 and 1.0, or n =1.0, for mass transfer following a
non-fickian model. In case of a cylinder n =0.45 instead of 0.5, and 0.89 instead of
1.0. This equation can only be used in systems with a drug diffusion coefficient
fairly concentration independent. To the determination of the exponent n the portion
of the release curve where Mt/M < 0.6 should only be used. To use this equation it
is also necessary that release occurs in a one-dimensional way and that the system
width-thickness or length-thickness relation be at least 10. A modified form of this
equation was developed to accommodate the lag time (l) in the beginning of the drug
release from the pharmaceutical dosage form:

When there is the possibility of a burst effect, b, this equation becomes:

In the absence of lag time or burst effect, l and b value would be zero and
only atn is used. This mathematical model, also known as Power Law, has been used
very frequently to describe release from several different pharmaceutical modified
release dosage forms.

Table 2. Interpretation of diffusional release mechanisms

Release exponent (n) Drug transport Rate as a function of
mechanism time

0.5 Fickian diffusion t-0.5

0.5<n<1.0 Anomalous transport tn - 1

 1.0 Case-II transport Zero-order release

Higher than 1.0 Super Case-II transport tn - 1

RESULTS AND DISCUSSION

The λ max of Eperisone hydrochloride was determined by running the spectrum of
drug solution in double beam ultraviolet spectrophotometer. The spectrum of this
solution was run 200-400nm range in U.V. spectrophotometer. The λ max of Eperisone
hydrochloride was found 272 nm. The standard solution of drug was prepared in
different conc. in 0.1 N HCl and plotted the graph between conc. and absorbance.
The plot of absorbance vs. concentration was plotted and on the absorption point the
linear line was determined. This follows Beer’s Lambert law. The linear regression
analysis was done on absorbance data points. The value of slope, intercept and
correlation coefficient were found to be 0.022, 0.020 and 0.998 respectively.
Important preformulation study includes identification of drug and excipients
followed by solubility analysis, Melting point, UV spectroscopy and FTIR
spectroscopy. In the present study showed color and odor of Eperisone HCl was
found white crystalline, odorless powder. It has been observed that Eperisone HCl
was freely soluble in methanol, ethanol, distilled water, soluble in chloroform and
0.1 N HCl, slightly soluble in 6.8 pH phosphate buffer and 0.1 N NaOH. The
percentage of loss on drying of Eperisone hydrochloride was found 0.247%. Melting
point of Eperisone hydrochloride was found 165-167°C. The Moisture content of
Eperisone hydrochloride was found 0.0458%.

Table 3. Solubility determination of Eperisone HCl in various solvent

Solvents Results of Solubility

Methanol Freely soluble
Ethanol Freely soluble
Chloroform Soluble
Distilled water Freely soluble
6.8 pH phosphate buffer Slightly soluble
0.1 N HCl Soluble
0.1 N NaOH Slightly soluble
Table 4. Loss on Drying
Drug % of LOD
Eperisone hydrochloride 0.247%
 Table 5. Melting point of Eperisone hydrochloride
S. No. Melting Point Result
Onset Complete
1 165 167
2 165 167
165-167°C
3 164 165

Figure 1: Determination of λmax of Eperisone HCl

Table 6. Calibration curve of Eperisone HCl

S. No. Concentration (µg/ml) Absorbance

1. 10
0.255
2. 20
0.475
3. 30
0.705
4. 40
0.894
5. 50
1.123
All values are expressed in S.D (n=3)
 Figure 2: Calibration curve of Eperisone HCl

Table 7. Statically data for linearity

S. No. Parameter Remark
1 Linearity Range 10-50 µg/ml
2 Regression Equation y = 0.022x + 0.020
3 Correlation Coefficient 0.998
FTIR spectroscopy of Eperisone HCl

Figure 3. FTIR Spectra of Eperisone hydrochloride

Table 8. Result of pre-compression properties of blend

Formulation Bulk Tapped Compressibility Hausner

code density(gm/ml) density(gm/ml) index ratio
F1 0.345 0.452 23.673 1.310
 F2 0.352 0.448 21.429 1.273

F3 0.347 0.458 24.236 1.320

F4 0.349 0.457 23.632 1.309

F5 0.352 0.462 23.810 1.313

F6 0.347 0.459 24.401 1.323

F7 0.336 0.448 25.000 1.333

F8 0.342 0.449 23.831 1.313

F9 0.348 0.441 21.088 1.267

Figure 4. Graph of pre-compression properties of blend

Table 9. Results of post compression properties of Eperisone HCl FGR tablets

Formulation Thickness* Hardnes* Weight Friability* (%) Drug Total Floating lag
2
code (mm) (kg/cm ) variation content* (%) floating times* (sec)
* (mg) duration*
(h)
F1 2.2±0.1 5.8±0.2 205±3 0.785±0.015 98.98±0.25 10±0.5 52±

F2 2.2±0.1 5.6±0.3 206±4 0.650±0.016 98.75±0.32 11±0.5 56±

F3 2.3±0.2 5.7±0.2 203±5 0.741±0.021 98.65±0.14 11±0.5 54±

F4 2.3±0.1 5.8±0.1 204±5 0.850±0.018 98.74±0.21 11±1 51±

F5 2.2±0.1 5.5±0.2 205±4 0.854±0.015 98.63±0.15 11±1 49±

F6 2.3±0.1 5.7±0.2 203±5 0.843±0.023 98.78±0.16 12±0.5 46±

F7 2.3±0.1 5.8±0.2 198±4 0.753±0.014 99.45±0.23 12±0.5 35±

F8 2.2±0.2 5.7±0.2 200±5 0.762±0.042 98.85±0.14 12±0.5 45±

F9 2.2±0.1 5.8±0.3 199±5 0.722±0.035 98.76±0.22 12±0.5 49±

*Average of three determinations (n=3)

Figure 5. Graph of post compression properties of FGR tablets

Table 10. In-vitro drug release study of GRF tablets

Time % Cumulative Drug Release

(hr) F1 F2 F3 F4 F5 F6 F7 F8 F9

0.5 45.56 42.25 39.98 43.32 39.98 35.56 20.23 18.85 15.52

1 65.58 60.45 56.65 62.23 56.65 55.45 26.65 23.32 20.23

1.5 88.89 76.65 73.32 79.98 76.62 65.58 39.98 32.25 25.45

2 95.56 88.89 82.23 88.85 82.23 79.98 46.52 39.98 33.65

3 99.21 93.32 90.23 98.85 98.18 88.85 58.89 46.65 41.45

4 -  98.85 98.78  - -  99.12 67.74 55.45 53.32

6  -  - -  -   - -  76.65 69.95 59.98

8  -  -  -  -  -  - 89.98 72.23 65.56

12  -  -  -  -  -  - 99.45 76.65 73.32

Figure 6. In-vitro drug release study of GRF tablets

Table 11. In-vitro drug release data for optimized formulation F7

Cumulati Log
Log
Square Cumulati ve % Cumulati
Cumulati
Time Root of Log ve*% Drug ve %
ve %
(h) Time(h)1 Time Drug Remainin Drug
/2 Drug
Release g Remainin
Release
g
0.5 0.707 -0.301 20.23 1.409 74.35 1.871

1 1 0 26.65 1.602 60.02 1.778

1.5 1.225 0.176 33.32 1.659 54.42 1.736

2 1.414 0.301 42.23 1.745 44.38 1.647

3 1.732 0.477 53.35 1.800 36.88 1.567

4 2 0.602 65.58 1.885 23.35 1.368

6 2.449 0.778 71.12 1.949 11.02 1.042

8 2.828 0.903 85.56 1.971 6.55 0.816

12 3.464 1.079 99.45 1.999 0.22 -0.658
 Figure 7. Cumulative % drug released Vs Time

Figure 8. Log cumulative % drug remaining Vs Time

 Figure 9. Cumulative % drug release Vs Root Time

Figure 10. Log Cumulative % drug release Vs Log Time

Table 12. Regression analysis data of Eperisone HCl floating tablets

 Zero Order First Order Higuchi Peppas
Batch
r²
F7 0.887 0.881 0.987 0.988

The % drug content of all the formulated tablets were found within the limit. % drug content
value of drug was within 98.65±0.14% to 99.45±0.23%.The results within the range indicate
uniform of mixing.
In vitro drug release studies were performed by using USP XXIII dissolution test apparatus II
at 50rpm using 900 mL of 1.2 pH buffer maintained at 37±0.5ºC as the dissolution medium.
Prepared optimized formulation (F7) showed the release of drug form gastroretentive
formulation 99.45% after 12 hrs. When the regression coefficient values of were compared, it
was observed that ‘r2’ values of korsmeyer peppas was maximum i.e. 0.988 hence indicating
drug release from formulations was found to follow korsmeyer peppas release kinetics.

CONCLUSION

Eperisone HCl floating gastro retentive tablet is developed using different polymers showed
desirable high-drug content and adequate release characteristics. The use of polymers like
HPMC in pharmaceutical dosage forms is of increasing interest due of their low production
cost, lesser toxic effects and regulatory acceptance. The gastroretentive floating tablets of
Eperisone HCl were formulated by using HPMC K4 and K15, showed pleasing results with
controlled drug released up to 12 h.

Acknowledgement: The authors thanks Abhitav Tiwari (Application Scientist), for their
constant scientific advice and technical support Acknowledges Zodprobe (The Research lab)
and Shri Ram institute of pharmacy Jabalpur Madhya Pradesh, for providing research
facilities.

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