Invitro : dissolution and drug release testing

In vitro : Dissolution and
drug release testing
Presented by:
Durgadevi.G
1st M.pharm.
Dept. of pharmaceutical analysis,
PSG college of pharmacy.

DISSOLUTION :
 Dissolution is a process in which a solid substance solubilizes
in a given solvent (mass transfer from the solid surface to the
liquid phase.)
 Dissolution testing measures the extent and rate of solution
formation from a dosage form, such as tablet, capsule,
ointment, etc.
 The dissolution of a drug is important for its bioavailability
and therapeutic effectiveness.

DISSOLUTION RATE :
 Dissolution rate is defined as the amount of solid
substance goes into solution per unit time under
standard conditions of temperature, pH and
solvent composition and constant surface area.
ABSOLUTE OR INTRINSIC SOLUBILITY :
 It is defined as the maximum amount of solute
dissolved in a given solvent under standard
conditions of temperature, pressure and pH.

DISSOLUTION OF TABLETS AND
CAPSULES
When a immediate release tablet or other solid drug
form is introduced into a beaker of water or into the
gastrointestinal tract, the following steps take place.
 Disintegration :
breaking of tablet into granules.
 Deaggregation :
breaking of these granules into individual particles.
 Dissolution :
finally, particles dissolve, releasing the active drug
into solution. Dissolution is a time dependant process
that represents the final step of drug release, which is
ultimately required before a drug can be absorbed or
exert a pharmacologic effect.

Name of Apparatus Drug product
Rotating basket tablets
Paddle Tablets, capsules, modified release
products, suspensions.
Reciprocating cylinder Extended release drug products
Flow cell Low water soluble drugs
Paddle over disk Transdermal drug products
Cylinder Transdermal drug products
Reciprocating disk Extended release drug products
Rotating disk Extended release drug products
OFFICIAL METHODS (USP) :

ROTATING BASKET METHOD
 Cylindrical basket of 22mesh.
 Rotating speed-100 rpm.
 As per IP, height of
dissolution jar is 168+8 mm
and internal diameter is
102+4 mm and height of basket
36.8+3 mm and diameter is
25.4+3 mm.
 Temp. maintained at 37ᵒC
 Calibration tablets of Prednisone-for disintegrating tablets.
 Salicylic acid calibration tablets-for non disintegrating tablets.
 For capsules & dosage forms that tend to float.

PADDLE METHOD
 It consists of a special coated paddle formed from a blade and
a shaft that minimizes turbulence due to stirring.
 The coated material is inert.
 The paddle is attached vertically to a variable -speed motor
that rotates at a controlled speed.

 As per IP, diameter of the paddle is 74.5+0.5 mm.
 The tablet or capsule is placed into a round-bottom
dissolution flask and the apparatus is housed in a
constant temperature water bath maintained at 37°C.
 Most common operating speeds are 50rpm for solid
oral dosage forms and 25 rpm for suspensions.
 A sinker ,such as few turns of platinum wire may be
used to prevent a capsule or tablet from floating
 Used for film coated tablets that stick to the vessel
walls or to help to position tablet/capsule under the
paddle.

RECIPROCATING CYLINDER METHOD
 Set of cylindrical, flat –bottomed glass vessels equipped with
reciprocating cylinders.
 temp. 37ᵒC
 Place the stated volume of dissolution medium in each vessel
of the apparatus, assemble the apparatus, equilibrate the
dissolution medium to 37±0.5ᵒC and remove the thermometer

 Place one dosage form unit in each of the
cylinders taking care to exclude the air bubbles
from the surface of each dosage unit and
immediately operate the apparatus as specified in
the monograph.
 During the upward and downward stroke, the
reciprocating cylinder moves through a total
distance of 9.9 to 10.1cm.
 Within the time interval specified raise the
cylinders and withdraw a portion of the solution
under test from a zone midway between the
surface of the dissolution medium and bottom of
each vessel.

FLOW THROUGH CELL METHOD
 The flow through cell is transparent & inert mounted vertically
with filters.
 Standard cell diameters are 12 & 22.6 mm.
 The bottom cone usually filled with glass beads of 1 mm
diameter. Place the glass beads into the cell as specified in the
monograph.
 Place one dosage unit on top of the beads or on a wire carrier.

 Tablet holder used for positioning special dosage
form e.g. inlay tablets.
 Assemble the filter head and fix the parts together
by means of a suitable clamping device.
 Introduce by the pump of the dissolution medium
warmed to 37±0.5ᵒC through the bottom of the
cell to obtain the flow rate specified and
measured with an accuracy of 5%.
 Flow rate is maintained from 4 to 16 mL /min.
 Collect the eluate by fractions at each of the
times stated
 For modified release dosage forms, containing
active ingredients with limited solubility.

PADDLE OVER DISK METHOD
 For testing the release of drug
from transdermal products.
 Stainless steel disk assembly is used
for holding the transdermal system at
the bottom of the vessel.
 The distance between the paddle
and the surface of the disk is kept 25 ± 2 mm .
 The release surface of the trans dermal patch is kept such that
it’s release surface faces upward and parallel to the edges of the
blade.
 The transdermal system may be attached to the disk assembly by
applying a suitable adhesive.
 TEMP.- 32± 0.5 ºC.
 Sample is drawn midway between the surface of the dissolution
medium and the top of the paddle blade.
Dosage unit
kept on disk
assembly

ROTATING CYLINDER METHOD
 Here, basket and shaft are replaced by the cylinder
stirring elements.
 The dosage unit is kept on the cylinder.
 The distance between the
inside bottom of the vessel and
the cylinder is kept at 25 ± 2 mm.
 TEMP .- 32± 0.5 ºC.
 Sample is mounted on to
cuprophan.
 Temperature 32ᵒC
 For testing transdermal preparations.
Inert porous
cellulose support

RECIPROCATING DISK METHOD
 It consist of a set of volumetrically calibrated or tared
containers of glass or other suitable inert material , a
motor and a set of sample holders.
 A motor drive assembly is used to
reciprocate the system vertically.
 Samples are placed on disk shaped
holders using cuprophan supports.
 Temperature 32ᵒC.
 Reciprocating frequency is about 30cylces per minute.
 It is useful for assessing the in vitro dissolution of
extended release tablets and transdermal drug delivery
systems

NON OFFICIAL METHODS
 Tumbling method
 Rotating disk method
 Rotating bottle method
 Intrinsic dissolution method
 Peristalsis method
 Sartorius apparatus
 Beaker method
 Dialysis method

TUMBLING METHOD
 In this method dosage form is
placed in tubes or bottles which
are rotated using revolving drum.
 It consists of magnetically driven rotating
filter assembly and a 12 mesh wire cloth
basket in which dosage form is placed.
 The sample is withdrawn through spinning
filter for analysis.
ROTATING FILTER METHOD

ROTATING DISK METHOD
 Developed by late eino nelson and described by Levy
and Sahli.
 Non disintegrating tablets or discs
mounted in plexiglas holder, one
surface exposed to the dissolution medium.
 Holder is attached to the metal shaft ,
free from vibration
 The tablet immersed one inch below the surface of 200
ml of dissolution fluid , temp 37ᵒc , in 500 ml three
round bottom flask , rate is 550 rpm.
 Samples were taken and assayed for drug content.

SARTORIUS APPARATUS
 It utilize in vivo stimulative method
 The absorption stimulater stimulates
passive drug transport process that occur
in vivo from GIT tract to plasma across
lipoidal mucosal barrier

ROTATING BOTTLE METHOD
 It consists of rotating rack to hold sample
drug products in bottles and they are
capped tightly and rotated in 37ᵒC
temperature bath
 Sample are decanted through a 40 mesh
screen and residue are assayed

INTRINSIC DISSOLUTION
METHOD
 Most method for dissolution deal with
finished drug product
 The dissolution of drug powder by
maintaining constant surface area is called
intrinsic dissolution.
 It is expressed as mg/cm²/min.

PERISTALSIS METHOD
 To stimulate hydrodynamic condition of
GIT tract in an in vitro dissolution device.
 It consists of rigid plastic cylindrical
tubing fitted with septum and rubber
stopper at both ends.
 Dissolution chamber consist of a space
between the septum and the lower stopper
 Dissolution medium pumped with
peristaltic action through the dosage form

BEAKER METHOD
 Reported by Levy and Hayes(1960)
 Dissolution medium , 250 ml of 0.1 N HCl at 37ᵒC placed in a 400
ml beaker
 Agitation by three blade polyethylene stirrer,5 cm diameter and
rotates at 60 rpm.
 Stirrer immersed to a depth of 2.7 cm in medium and in the center
 Samples are removed and assayed for the content.

DIALYSIS METHOD
 Cell consist of 32 mm inflated membrane
 Plugged at the lower end by tight fitting cylindrical perspex
box.
 Upper end of the tube held by thin perspex ring inserted into
the tube and secured by an elastic band
 The cell , suspended from the arm of a tablet disintegration
apparatus and containing the dosage form in 50 ml of distilled
water at 37ᵒC.
 The cell was raised and lowered 30 times a min into 150 ml
of distilled water at same temp.
 Agitation by slight flexing and streching of the dialysis
membrane as it enters and leave the bath
 Rotation at 60 rpm
 Samples taken and assayed for content.

ALTERNATIVE METHODS OF DISSOLUTION
TESTING TRANSPORT MODELS
NON SINK METHODS
For poorly water-soluble drugs, pharmaceutical scientists are increasingly
applying in vitro dissolution testing under non-sink conditions for a direct
evaluation of their ability to generate and maintain supersaturation as a predictive
surrogate for ensuring product quality and in vivo performance.
NATURAL CONVECTION NON SINK METHODS:
a) Klein solvmeter method
b) Nelson hanging pellet method
c) Levy static disk method
FORCED CONVECTION NON SINK METHODS:
a)Tumbling method
b) Levy or Beaker method
c) Rotating disk method
d) Particle size method
e) USP Rotating basket apparatus
f) USP Paddle apparatus

SINK METHODS
Sink condition is the ability of the dissolution media to dissolve at
least 3 times the amount of drug that is in your dosage form.
Having sink conditions helps your dissolution have more robustness
as well as being more biologically relevant.
FORCED CONVECTION SINK DEVICES:
a) Wurster pollis adsorption method
b) Partition method
c) Dialysis methods
d) Rotating disk apparatus
CONTINOUS FLOW/FLOW THROUGH METHODS:
a) Pernarowski method
b) Langenbucher method
c) Baun and Walker
d) Tingstad and Reigelman
e) Modified column apparatus
f) Takenaka method

KLEIN SOLVMETER
METHOD
 Carrier device surrounded by flat and is immersed in
dissolution medium
 When dosage form is placed in the boat the bar moves
and as dosage form dissolves it moves upwards
 Amount of dosage form dissolved is revealed from the
difference in height of bar movement

NELSON HANGING PELLET
METHOD
 Aluminum strip having provision for holding dosage
form which is in turn connected perfectly maintained
balance arm of strip
 Dosage form is mounted on aluminium strip with help of
wax .This method can be employed to know Intrinsic
dissolution rate.
 To prevent disintegration further high pressures can be
applied and also constant surface

LEVY STATIC DISK METHOD
 Acrylic holder containing dosage form is inserted
into a known volume of medium through rubber
stopper
 The vial is inverted and placed in incubator at 37 C .
 At specific time intervals the vial is removed from
incubator and samples are analysed
 Disadvantages :- effect of conc. On dissolution
medium is ignored and the surface area of dosage
form while dissolving is assumed constant which is
not impractical.

WURSTER-POLLI ADSORPTION
METHOD
 In this method the dissolved drug is
adsorbed by charcoal or bentonite. care
should be taken regarding the adsorbent,
adsorbent should not alter the viscosity of
the medium

PARTITION METHOD
 In this device organic phase is employed
to remove the dissolved drug such that the
drug would partition between the
lipophilic and hydrophilic phases.
selection of organic phase plays a critical
role

ROTATING FLASK APPARATUS
 In this method a flask containing dissolution medium is
rotated around its horizontal axis in a water bath kept at
a temperature of 37 C.
 The flask has a provision of sampling such that aliquots
can be withdrawn and the fresh medium can be replaced
back.
 This apparatus is best suited for oral solid dosage forms
like tablets and capsules since they do not require much
agitation.

FLOW THROUGH DEVICES
 For the drugs which saturate rapidly in large
volumes of medium, USP apparatus will not
serve the purpose.
 For this the suitable device is flow through
device. In this device unlimited quantity of fresh
dissolution is available.
 A dosage form is placed in a small cell and is
subjected to a stream of fresh dissolution
media.

PERNAROWSKI
 It consists of 10 mesh stainless steel
basket stirrer assembly with an adjustable
stirrer.
 the chamber is 3 necked flask of 33 mm
and the rest two of 20 mm diameter.
 1L of medium is employed within the
flask.
 the dissolution characteristics are
dependent upon the amount of medium
pumped through the dissolution chamber.

LANGENBUCHER COLUMN TYPE
 This device is according to the
dissolution basic design .
 The screen is constructed such that the
medium flows equally through the entire
cross section in a laminar pattern.
 This is again closed by a secondary
screen, filter which prevents the
undissolved drug from being eluted.

TINGSTAD AND RIEGELMAN
 a cylindrical glass cell of 6.1 cm long and 1.9 cm in
diameter constructed with two glass filter funnels is
used.
 The dissolution cell has filter membranes which
prevents the solid particles from being analyzed.
 There are also external valves to control the excess flow
of solvent into the system. the air trap averts air bubbles.
 The complete assembly is
immersed in a temperature bath
kept at 37ᵒC

MODIFIED COLUMN APPARATUS
 The device consists of filter of 14 M -size made of
nylon.
 the tubing from the pump is connected to the dissolution
cell.
 the Teflon faced stainless steel supports the screen
resting on the bottom half of the filter holder.
 The direction of the flow is
such that the particles do not fall
through the screen. the rest of the
process is the same.

TAKENAKA
 The release of drug is measured with the aid of in vitro
simulator device consisting of flow type dissolution
container.
 The dosage form is placed in the basket rotating at 94
rpm with 300 ml of medium.
 then the medium is removed by collecting reservior
using peristaltic pump.
 aliquots are withdrawn using syringe and then filtered
using Whatman filter paper and the same volume is
replaced immediately with fresh medium.

IN VITRO DISSOLUTION AND DRUG RELEASE
STUDY INVOLVES :
 Preparation of solutions for calibration curve
 Stock solution
 Sample solution
 Buffer solution
 Determination of absorption maxima
 Preparation of calibration curve
 Dissolution study
 Dissolution procedure was carried out.
 Plot a graph between Time intervals on x-axis vs %
of drug release on y-axis.
 Find out the slope, concentration, amount of drug
release, percentage of drug release and report it.

DRUG RELEASE TESTING
 Drug release is the process by which a drug leaves
a drug product
 Drug release :
 Immediate release (IR)
 Sustained Release (SR)
 Sustained Action (SA)
 Extended Release (ER)
 Long Acting (LA)
 Prolong Action (PA)
 Controlled Release (CR)
 Timed Release (TR)

 Immediate release drug products allow drugs to
dissolve with no intention of delaying or prolonging
dissolution or absorption of the drug
 Prolonged-release dosage forms Prolonged-release
dosage forms are modified-release dosage forms
showing a slower release of the active substance(s) than
that of a conventional-release dosage form
administered by the same route.
 Delayed release is defined as the release of a drug at a
time other than immediately following administration.
 Enteric Coated: Intended to delay the release of the
drug (or drugs) until the dosage form has passed
through the stomach. Enteric-coated products are
delayed-release dosage forms.

 Controlled release includes extended-release and
pulsatile-release products
Extended-release products are formulated to
make the drug available over an extended period
after administration.
Pulsatile release involves the release of finite
amounts (or pulses) of drug at distinct time
intervals that are programmed into the drug
product.
 Repeat action products contain two single doses
of medication; one for immediate release; another
one for modified release

 Targeted release drug release directed toward
isolating or concentrating a drug in a body
region, tissue or site of absorption or for drug
action Drug release and dissolution
 Modified-release dosage forms include both
delayed and extended-release drug
productsModified-release dosage forms are
preparations where the rate and/or place of
release of the active substance(s) is different
from that of a conventional- release dosage
form administered by the same route.

APPARATUS FOR DRUG RELEASE TESTING OF
VARIOUS DOSAGE FORMS :
DOSAGE FORM EXAMPLE RELEASE METHOD
Oral solid dosage forms Basket apparatus, paddle apparatus,
reciprocating cylinder, flow through cell
Oral suspensions Paddle apparatus
Oral disintegrating tablets Padder apparatus, disintegration method
Chewable tablets Basket apparatus, paddle apparatus,
reciprocating cylinder
Powders and granules Flow through cell
Thin dissolvable films Basket apparatus, disintegration method
Chewing gum Special apparatus
Dermal delivery systems(patches) Paddle over disk
Topical (semisolid dosage forms) Franz cell diffusion system
Suppositories Paddle apparatus, modified basket
apparatus
Microparticulate formulations Modified flow through cell
Implants Modified flow through cell
Aerosols Cascade impactor

IN VITRO DRUG RELEASE TESTING
ROTATING BASKET METHOD :
 In vitro release study was carried out by the
rotating basket method.
 Six tablets of each batch were taken and placed in
rotating basket, respectively.
 Then the rotating basket was introduced into 900
mL of each dissolution medium (water, 0.1 M HCl
and pH 6.8 phosphate buffer) at 37˚C ± 0.5˚C
with a rotation speed of 100 rpm.
 5 mL of sample solution was collected at
different time intervals (2, 4, 6, 8, 10, 12 h) and
filtered through a 0.45 µm hydrophilic membrane.

 1.0 mL of subsequent filtrate was taken accurately to
add into a 100 mL volumetric flask and diluted with the
corresponding dissolution medium to 100 mL and
mixed well.
 The amount of drug dissolved in the dissolution
medium was measured using an UV-visible
spectrophotometer at 233 nm.
 The same volume of fresh dissolution medium at the
same temperature was added to replace the amount
withdrawn after each sampling.
 The drug amount of cumulative release was calculated
with a standard curve.

Invitro : dissolution and drug release testing

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