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SUSTAINED RELEASE DOSAGE FORM: A CONCISE REVIEW

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INTERNATIONAL JOURNAL OF PHARMACEUTICS & DRUG ANALYSIS
VOL.5 ISSUE 5, 2017; 153 – 160 ; http://ijpda.com; ISSN: 2348-8948

goal in designing sustained release delivery sys-

Review Article
tems is to reduce frequency of dosing or to increase
effectiveness of the drug by localization at the site
SUSTAINED RELEASE of the action, reducing dose required or providing
uniform drug delivery.The ideal drug delivery sys-
DOSAGE FORM: A tems have two things would be required first it
CONCISE REVIEW would be a single dose the duration of treatment
whether it is for days or week, as with infection, or
for the life time of the patient, as in hypertension or
Darandale Abhishek S1. Ghule Prashant J2 diabetes. Second it should deliver the active entity
Aher Abhijit A1, Narwate B.M1.
directly to the site of the action, thereby minimiz-
ing side effects.1
1. MES's College Of Pharmacy Sonai
2. Mula Rural Institute of Pharmacy Sonai DISADVANTAGES OF CONVENTIONAL DO-
SAGE FORMS
Date Received: 13th April 2017; Date accepted: 1. Poor patient compliance, increased chances of
missing the dose of a drug with short half-life for
29th April 2017; Date Published: 2nd May 2017
which frequent administration is necessary.
Abstract
2. The unavoidable fluctuations of drug concentra-
Now days as the expense and complications in- tion may lead to under medication or over medica-
volved in marketing new drug entities are in- tion.
creased, with concomitant recognition of the the-
3. A typical peak-valley plasma concentration time
rapeutic advantages of controlled drug delivery,
profile is obtained which makes attainment of
greater attention has been focused on development
steady-state condition difficult.
of sustained or controlled release drug delivery
systems (DDS). Hence we will change the area of 4. The fluctuations in drug levels may lead to pre-
focusing it is suitable to designing sustained drug cipitation of adverse effects especially of a drug
delivery is to reduce the frequency of dosing or to with small Therapeutic Index whenever over me-
increase the effectiveness of the drug by localiza- dication occur [1, 6, 7].
tion at the site of action, reducing the dose re-
ADVANTAGES OF SUSTAIN RELEASE DO-
quired or providing uniform drug delivery. The
SAGE FORMS
design of oral sustained release DDS depends on
various factors such as, physicochemical properties 1. Reduction in frequency of intakes.
of drug, type of delivery system, disease being
2. Reduce side effects.
treated, and patient condition, and treatment dura-
tion, presence of food, gastrointestinal motility, and 3. Uniform release of drug over time.
co-administration of other drugs. 4. Better patient compliance [1, 5, 8].
Keywords: Sustained release drug delivery system, DISADVANTAGES OF SUSTAINED RELEASE
Dose frequency, Biological half-life, physicochemi- DRUG DELIVERY
cal properties of drugs.
1. Increased cost.
Introduction
2. Toxicity due to dose dumping.
Sustained release, sustained action, prolonged ac-
tion controlled release, extended release, depot 3. Unpredictable and often poor in vitro-in vivo cor-
release these are the various terms used to identify relation.
drug delivery systems that are designed to achieve 4. Risk of side effects or toxicity upon fast release
a prolonged therapeutic effect by continuously of contained drug (mechanical failure, chewing or
releasing medication over a long period of time masticating, alcohol intake).
after administration of a single dose of drug. The

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5. Increased potential for first- pass clearance. device,the rate of drug released (dm/dt) can be
calculatedusing the following equation:
6. Need for additional patient education and coun-
seling [9-11]. Dm/dt=ADK∆C/1
CLASSIFICATION OF ORAL SUSTAINED OR Where,
CONTROLLEDRELEASE SYSTEMS
A = Area
The controlled release systems for oral use are
D = Diffusion coefficient
mostly solidsand based on dissolution, diffusion or
a combination of bothmechanisms in the control of K = Partition coefficient of the drug between the
release rate of drug. Dependingupon the manner drug core and the
of drug release, these systems areclassified as fol- membrane
lows:
L = Diffusion path length and
1. Continuous release systems
C = Concentration difference across the membrane
2. Delayed transit and continuous release systems
In order to achieve a constant release rate, all of
3. Delayed release systems theterms on the right side of equation must be held
constant.It is very common for diffusion controlled
1. Continuous release systems
devices toexhibit a non-zero-order release rate due
Continuous release systems release the drug for to an increasein diffusional resistance and a de-
aprolonged period of time along the entire length crease in effectivediffusion area as the release
of proceeds. Anotherconfiguration of diffusion-
controlled systems includesmatrix devices, which
gastrointestinal tract with normal transit of the
are very common because of easeof fabrication.
dosageform. The various systems under this cate-
Diffusion control involves dispersion ofdrug in
gory are asfollow:
either a water-insoluble or a hydrophilic poly-
A. Diffusion controlled release systems mer.The release rate is dependent on the rate of
drugdiffusion through the matrix but not on the
B. Dissolution controlled release systems
rate of soliddissolution.
C. Dissolution and diffusion controlled releasesys-
The two types of diffusion-controlled release are:
tems
a. Matrix diffusion controlled systems
D. Ion exchange resin- drug complexes
b. Reservoir devices
E. pH-independent formulation
B. Dissolution-controlled release systems[1]
A. Diffusion controlled release systems
The drug present in such system may be the one:
In this type of systems, the diffusion of dissolved
drugthrough a polymeric barrier is a rate limiting a. Having high aqueous solubility and dissolution
step. Thedrug release rate is never zero-order, since rate
thediffusional path length increases with time as
b. With inherently slow dissolution rate e.g. Gri-
the insolublematrix is gradually depleted of drug.
seofulvin and Digoxin
Diffusion of a drugmolecule through a polymeric
membrane forms the basisof these controlled drug c. That produces slow dissolving forms, when it
delivery systems.Similar to the dissolution- comes in contact with GI fluids
controlled systems, the diffusioncontrolleddevices
Dissolution-controlled release can be obtained by
are manufactured either byencapsulating the drug
slowing the dissolution rate of a drug in the GI
particle in a polymeric membraneor by dispersing
medium, incorporating the drug in an insoluble
the drug in a polymeric matrix. Unlikethe dissolu-
polymer and coating drug particles or granules
tion-controlled systems, the drug is madeavailable
with polymeric materials of varying thickness. The
as a result of partitioning through the polymer.In
rate limiting step for dissolution of a drug is the
the case of a reservoir type diffusion controlled

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diffusion across the aqueous boundary layer. The tric acid, amino acid,tartaric acid can be added to
solubility of the drug provides the source of energy the formulation, to help tomaintain to constant pH
for drug release, which is countered by the stag- their by retarding Phindependent drug release. A
nant-fluid diffusional boundary layer. buffer sustain releaseformulation is prepared by
mixing a basic or acidic drugone or more buffering
The rate of dissolution (dm/dt) can be approx-
agent, granulating withappropriate excipients and
imated by following equation:
coating with gastrointestinalfluid permeable film
dm forming polymer. Whengastrointestinal fluid per-
meates through the membrane, the buffering agent
dt = ADS
adjusts the fluid inside to suitableconstant pH
h there by rendering a constant rate of drugrelease.
Where, F. Osmotic pressure controlled systems [7]
A = Surface area of the dissolving particle A semi permeable membrane is placed around the-
or tablet tablet, particle or drug solution that allows trans-
port ofwater into tablet with eventual pumping of
D = Diffusivity of the drug drug solutionout of the tablet through the small
S = Aqueous solubility of the drug delivery aperture intablet core. Two type of osmot-
ic pressure controlledsystems are:
h = Thickness of the boundary layer
a. Type 1 contains an osmotic core with drug
The two types of dissolution-controlled release are:
b. Type 2 contains the drug in flexible bag withos-
A. Matrix (or monolith) dissolution controlled sys- motic core surroundingBy optimizing formulation
tems and processing factor, it ispossible to develop os-
B. Reservoir dissolution controlled systems motic system to deliver the drug ofdiverse nature
at preprogrammed rate.
C. Dissolution and diffusion controlled release
systems [6] 2. Delayed transit and continuous release systems
[1, 4]
In such systems, the drug core is encased in a par-
tially soluble membrane. Pores are thus created These systems are designed to prolong their resi-
due to dissolution of parts of the membrane which dence inthe GI tract along with their release. Often
permit entry of aqueous medium into the core and the dosageform is fabricated to detain in the sto-
hence drug dissolution and allow diffusion of dis- mach and hence thedrug present therein should be
solved drug out of the system. stable to gastric pH.Systems included in this cate-
gory are mucoadhesivesystems and size based sys-
D. Ion exchange resin-drug complexes [8] tems.
It is based on formulation of drug resin complex 3. Delayed release systems [1]
formed when ionic solution is kept in contact with
ionic resins. The drug from this complex gets ex- The design of such systems involves release of
changed in gastrointestinal tract and released with drug onlyat specific site in the GIT. The drugs con-
excess of Na+ and Cl- present in gastrointestinal tained in such asystem are those that are:
tract. This system generally utilize resin compound a. Known to cause gastric distress
of insoluble cross linked polymer. They contain salt
forming function group in repeating position on a b. Destroyed in the stomach or by intestinalen-
polymer chain. zymes.

E. pH-independent formulation [19] c. Meant to extent local effect at a specific GI site

Most of the drug are either weak acid or weak d. Absorbed from a specific intestinal site
base, therelease from sustain release formulation is The two types of delayed release systems are:
pH dependent.However, buffer such as salt of ci-
1. Intestinal release systems

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2. Colonic release systems Drug-candidates suitable for sustained release

products
Rationale of controlled drug delivery system
For a successful sustained-release product, the
The basic rationale for controlled drug delivery is
drug must be released from the dosage form at
to alter the pharmacokinetics and pharmacody-
apredetermined rate, dissolve in the gastrointestin-
namics of pharmacologically active moieties by
al fluids, maintain sufficient gastrointestinal resi-
using novel drug delivery systems or by modifying
dence time, and be absorbed at a rate that will re-
the molecular structure and/or physiological pa-
place the amount of drug being metabolized and
rameters inherent in a selected route of administra-
excreted.Zero order oral drug release can be
tion. Thus, optimal design of controlled release
achieved, in principle, by surrounding a core tablet
systems necessitates a thorough understanding of
with a membrane that is permeable to both drug
the pharmacokinetics and pharmacodynamics of
and water, as illustrated in Fig 3a. After swallow-
drug [15].
ing, the core becomes hydrated, and drug dissolves
However, when doses are not administered on until it reaches its saturation concentration or solu-
schedule, the resulting peaks and valleys reflect bility. The core serves as a saturated reservoir of
less drug. Drug release proceeds by partitioning from
the reservoir into the membrane, followed by dif-
than optimum drug therapy. For example, if doses
fusion across the membrane into the gastrointes-
are administered too frequently, minimum toxic-
tinal fluid. So long as saturation is maintained in
concentration (MTC) of drug may be reached with
the core, there will be a stationary concentration
toxic side effects resulting. If doses are missed, pe-
gradient across the membrane, and release will
riods of sub-therapeutic drug blood levels or those
proceed at constant rate. Eventually, the dissolved
below the minimum effective concentration (MEC)
drug’s concentration in the core falls below satura-
may result, with no patient benefit. Extended re-
tion, reducing the concentration gradient andhence
lease tablets and capsules are commonlytaken only
the release rate, which decays to zero. If the mem-
once or twice daily compared with counterpart
brane consists of a water-soluble polymer of high
conventional forms that may need to betaken three
molecular weight, then it will initially swell into a
to four times daily to achieve the same therapeutic
gel,through which drug diffuses. The thickness of
effect. Typically, extended release products provide
the gel layer initially increases with time due to
an immediate release of drug which then is fol-
swelling, but ultimately it decreases due to disen-
lowed by the gradual and continual release of ad-
tanglement and dissolution of polymer chains. At
ditional amounts of drug to maintain this effect
intermediate times, the gel layer may be of approx-
over a predetermined period of time (Fig 1)
imately constant thickness, and release occurs at a
relatively constant rate.
As an alternative to dissolution/partition/diffusion
based devices, osmotic pumps have been devel-
oped to provide zero order release. An elementary
osmotic pump, illustrated in Fig 3, is a tablet or
capsule consisting of a core of drug surrounded by
a membrane that is permeable to water but not to
the drug. A small hole is drilled into the mem-
brane. Upon ingestion, water is osmotically im-
Figure 1.Characteristic representation of plasma
bibed into the core through the semi permeable
concentrations of a conventional immediate re-
membrane, dissolving the drug. A constant osmot-
lease dosageform (IR), a sustained release dosage
ic pressure gradient is established between core
form (SR) and an idealized zero-order controlled
and the external medium, setting the stage for wa-
release (ZOCR) dosage form (in combination
ter influx, which displaces drug through the hole at
with a start-up dose).
a constant rate. Eventually, drug concentrationfalls
below its solubility, and the rate of osmotic pump-

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ing decays. The efficiency of osmotic devices can b) Solubility:

be improved by enriching the core with excipients
Solubility of drug was determined in pH 1.2 and
such as water soluble polymers. For example, in
pH 6.8 buffers. Solubility Studies wereperformed
push-pull osmotic systems, depicted in Fig 3c, the
by taking excess amount of drug in beakers con-
drug formulation is layered between the water so-
taining the Solvents. The mixtures were shaken for
luble polymer and the exit orifice. As water crosses
24 hrs at regular intervals. The solutions were fil-
the semi permeable membrane, drug is dissolved.
tered by using whattmann’s filter paper grade no.
Meanwhile, swelling of the polymer excipients,
41. The filtered solutions are analysed spectropho-
which is also caused by osmosis, pushes drug
tometrically at 260.5nm as pH 1.2 as blank and
through the orifice
262.4nm as pH 6.8 as blank.
c) Compatibility Studies:
Compatibility study with excipients was carried
out by FTIR. The pure drug and its formulations
along with excipients were subjected to FTIR stu-
dies. In the present study, the potassium bromide
disc (pellet) method was employed
d) Identification of Drug:
Weigh accurately about 0.25 gm, dissolve in 50 ml
of carbon dioxide-free water and titrate with 0.1 M
sodium hydroxide using phenol red solution as
Figure 2.Schematics of devices designed for zero- indicator. Repeat the operation without the sub-
order drug release. stance under examination. The difference bet-
weenthe titrations represents the amount of so-
(a) Membrane diffusion controlled release. Drug in
dium hydroxide required.
core (granulated pattern) dissolves to form satu-
rated solution (dilute dots). Drug then diffuses Methods for Preparation of Controlled Release
across membrane (thin tipped arrows).
tablets[19]
(b) Elementary osmotic pump. Core is surrounded
1) Wet Granulation Technique
by a semipermeable membrane, with a small,
drilled orifice. i) Milling and gravitational mixing of drug, po-
lymer and excipients.
(c) Push–pull osmotic pump.
ii)Preparation of binder solution
PREFORMULATION STUDIES
iii) Wet massing by addition of binder solution or
Preformulation testing is an investigation of physi-
granulating solvent
cal and chemical properties of drug substances
alone and when combined with pharmaceutical iv) Screening of wet mass.
excipients. It is the first step in the rational devel-
v) Drying of the wet granules.
opment of dosage form.
vi) Screening of dry granules
a) Determination of Melting Point:
vii) Blending with lubricant and disintegrant to
Melting point of drug was determined by capillary
produce “running powder”Compression of tablet.
method. Fine powder of drug was filled in a glass
capillary tube (previously sealed at one end). The 2) Dry Granulation Technique
capillary tube is tied to thermometer and the ther- Milling and gravitational mixing of drug ,
mometer was placed in the Thais tube and this polymer and excipients
tube is placed on fire. The powder at what temper- Compression into slugs or roll compac-
ature it will melt was noticed. tion

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Milling and screening of slugs and com- Dt = M / Vt

pacted powder
Where,
Mixing with lubricant and disintegrant
Compression of tablet. Dt = Tapped density (gm/cc)

3) Sintering Technique M = mass of powder (g)

Sintering is defined as the bonding of ad- Vt=tapped volume of powder (cc)

jacent particle surfaces in a mass of
C. Compressibility index:
powder, or in a compact, by the applica-
tion of heat. The compressibility of thepowder was determined
Conventional sintering involves the heat- by the Carr’s compressibilityindex.
ing of a compact at a temperature below Carr’s index (%) = = b=(v/b) X100
the meltingpoint of the solid constituents
in a controlled environment under at- Table 1.Grading of powders for their flow pro-
mospheric pressure. pertiesaccording to carr’s index
The changes in the hardness and disinte- Sr. No Carr’s Index Flow Properties
gration time of tablets stored at elevated
temperatureswere described as a result of 1 5-15 Excellent
sintering. 2 12-15 Good
The sintering process has been used for
3 18-21 Fair to Passable
the fabrication of sustained release matrix
tablets for the stabilization of drug re- 4 23-30 Poor
lease. 5 33-38 Very Poor
Evaluation Parameters 6 >40 Very Very Poor
1) Pre Compression Parameters:
D. Hausner ratio:
A. Bulk density (Db):
Hausner ratio = tapped density/bulk density
It is the ratio of powder tobulk volume. The bulk
density depends on particle sizedistribution, shape Values of Hausner ratio; < 1.25: good flow
and cohesiveness of particles.Accurately weighed >1.25: poor flow
quantity of powder was carefullypoured into
If Hausner ratio is between 1.25-1.5, flow can
graduated measuring cylinder throughlarge funnel
beimproved by addition of glidants.
and volume was measured which is calledinitial
bulk volume. Bulk density is expressed in E. Angle of repose (θ):
gm/ccand is given by,
It is defined as the maximumangle possible be-
Db = M / Vo tween the surface of pile of thepowder and the
horizontal plane. Fixed funnel methodwas used. A
Where,
funnel was fixed with its tip at a givenheight (h),
Db = Bulk density (gm/cc) above a flat horizontal surface on which agraph
M = mass of powder (g) paper was placed. Powder was carefully poured

Vo= bulk volume of powder (cc) through a funnel till the apex of the conical pile
justtouches the tip of funnel. The angle of repose
B. Tapped density (Dt): was thencalculated using the formula,
Ten grams of powder wasintroduced into a clean, Tanθ =h/r
dry 100ml measuring cylinder.The cylinder was
then tapped 100 times from aconstant height and θ = tan-1(h/r)
tapped volume was read. It isexpressed in gm/cc where, θ = angle of repose,
and is given by,

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h = height of pile, The weight of the tablet being made in routinely-

measured to ensure that a tablet contains the pro-
r = radius of the base of the pile.
peramount of drug. The USP weight variation test
Table 2.Comparison between angles of reposes wasdone by weighing 20 tablets individually, cal-
and flowproperty culatingthe average weight and comparing the
individualweights to the average. The tablet meet
Sr. No. Angle of repose Flow properties
the USP test ifnot more than 2 tablets are outside
1 <25 Excellent
the percentagelimits and if no tablets differs by
2 25-30 Good
more than 2 times thepercentage limit. USP official
3 30-40 Passable limits of percentagedeviation of tablet are pre-
4 >40 Very Poor sented in the following table,

F. Total Porosity: Total porosity was determined Table 3.Weight variation limits
bymeasuring the volume occupied by a selected
weight ofa powder (Vbulk) and the true volume of
the powderblend (The space occupied by the Sr. Average weight Maximum % of dif-
powder exclusive ofspaces greater than the inter- No. of tablet (mg) ference allowed
molecular spaces, V). 1 10
130 or less
Porosity (%) =Vbulk-V/Vbulkx 100 2 7.5
130-324
G. Flow rate:
3 5
Flow rate of granules influences thefilling of die 324 or more
cavity and directly affects the weight of thetablets
produced.
2. Post Compression Parameters

A. Thickness and diameter:

Where, PD = Percentage deviation,
Control of physical dimension of the tablet such
W avg = Average weight of tablet,
asthickness and diameter is essential for consume-
racceptance and tablet uniformity. The thickness W initial =individual weight of tablet.
anddiameter of the tablet was measured using E. Uniformity of drug content:
Verniercalipers. It is measured in mm.
Five tablets of various formulations were weighe-
B. Hardness: dindividually and powdered. The powder equiva-
The Mansanto hardness tester was used to deter- lent toaverage weight of tablets was weighed and
minethe tablet hardness. The tablet was held be- drug wasextracted in Phosphate buffer pH 6.8, the
tween afixed and moving jaw. Scale was adjusted drug contentwas determined measuring the absor-
to zero; loadwas gradually increased until the tab- bance at 262.4 nmafter suitable dilution using a
let fractured. The value of the load at that point UV/VisibleSpectrophotometer (UV-1800).
gives a measure ofhardness of the tablet. Hardness CONCLUSION
was expressed inKg/cm2.
Oral Sustained release (S.R) / Controlled release
C. Friability (F): (C.R) products provide an advantage over conven-
tional dosage forms by optimizing bio-
Tablet strength was tested by Friabilator USP EF-2.
pharmaceutics, pharmacokinetic and pharmaco-
Preweighed tablets were allowed for 100 revolu-
dynamics properties of drugs in such a way that it
tions(4min), taken out and were dedusted. The reduces dosing frequency to an extent that once
percentageweight loss was calculated by rewriting daily dose is sufficient for therapeutic management
the tablets. The% friability was then calculated by, through uniform plasma concentration providing
maximum utility of drug with reduction in local
D. Weight variation test :
and systemic side effects and cure or control condi-

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tion in shortest possible time by smallest quantity controlled drug deliverysystem, Chapter 7,
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the design and performance of sus- Lee V. H. L.(Eds.), Marcel Dekker Inc., New
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York, 1978, 29,p. 254, 373
suitable illustrations.
11. Ansel C.H., Pharmaceutical Dosage Forms and
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