QC 2 LAB DISINTEGRATION / DISSOLUTION

DISSOLUTION

A test to measure the release of the active substance API from solid oral dosage dorms (tablets &
capsules)
It is one of the most important and useful in vitro test for assuring product quality
In vitro dissolution test often aids in guiding the selection of prototype formulations
It helps in the determination of optimum amounts of ingredient needed to achieve requisite drug
release profiles
Provides information on the impact of changes in composition, process or site of manufacture
Can help in the data on bioavailability/absorption following administration
In vitro dissolution is a valuable tool to assess drug product stability and shelf life
As the product age, the formulation properties may change and alter the dissolution characteristics of
product over time
o Moisture levels may increase or decrease over time and this can result in altered tablet
hardness
o Polymorphic transformations that will affect the solubility and dissolution

DISSOLUTION PATH OF SOLID DOSAGE FORMS

Dosage Form Disintegration Granules Deaggregation Dissolution

INTRINSIC DISSOLUTION

The rate of dissolution of a pure pharmaceutical active ingredient when condition such as
o Surface area
o Temperature
o Agitation or stirring speed kept constant
o pH
o Ionic Strength
This parameter allows the screening under various biophysiological conditions

FACTORS INFLUENCING DISSOLUTION AND DISSOLUTION STUDIES

Physiochemical Properties of Drug

Factors Relating Dissolution Apparatus
Factors Relating Dissolution Media

Physiochemical Properties of Drug

o Drug Solubility
Solubility of drug plays a prime role in controlling its dissolution from dosage form
o Particles Size
There is a direct relationship between surface areas of drug and its dissolution rate.
Surface area increases with the decrease in articles size
Surface Area Particles Size
Higher dissolution rates may be achieved through reduction of particles size
Micronization of sparingly soluble drug to reduce particles size is by no means a
guarantee of better dissolution and bioavailability
o Salt formation
It is one of the common approaches used to increase drug solubility and dissolution
rate
It has always been assumed that sodium salts dissolves faster than their corresponding
insoluble acids
Eg. Sodium and potassium salts of Pen-G, sulfa drugs, phenytoin, barbiturates
etc.

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

o Solvates and Hydrates

A solvate is a molecular complex that has incorporated the crystallizing solvent
molecules into specific sites within the crystal lattice
If the solvent is water, it is called hydrate
Anhydrous compounds are highly soluble than hydrate compound
Anhydrous > Hydrate
o pH effect
The solubility of a weak acidic drug or weak basic is influenced by the pH of the fluid
Rate of dissolution is increased while increasing the pH solution
pH Rate of dissolution
Eg. Penicillin, Aspirin in alkaline buffered tablets dissolution
o Adsorbents
The concurrent administration of drugs and medicinal products containing solid
absorbents (anti-diarrhoeal mixtures) may result in the adsorbents of such drugs from
the GIT
Eg. Promazine adsorbs an attalpulgite decrease absorption
Factors Relation Dissolution Apparatus
o Size and Shape
o Stirring device
o Vibrations
o Alignment of the Stirring elements
o Temperature

Factors Related to Dissolution Media

o pH of dissolution media
o Surface Tension
o Viscosity

o Nature of medium
APPARATUS NAME DRUG PRODUCT
IP USP BP EP Apparatus
Rotating Basket Tablets
Type Paddle Basket Basket Basket 1
1 Apparatus Apparatus Apparatus Apparatus
Tablet, Capsules,
Type Basket Paddle Paddle Paddle Apparatus Modified Drug
Paddle
2 Apparatus Apparatus Apparatus Apparatus 2 Products,
Suspensions
Flow Flow
Type Reciprocating Apparatus Reciprocating Extended Release
Through Through
3 Cylinder
Cell Cell 3 Cylinder Drug Products
Drug Products
Apparatus Containing Low-
Type Flow Through Flow Cell
4 Water Soluble
4 Cell
Drugs
Apparatus Transdermal Drug
Type Paddle Over Paddle over disk
5 Products
5 Disk
Apparatus Transdermal Drug
Type Rotating Cylinder
6 Products
6 Cylinder
Apparatus Transdermal Drug
Reciprocating Disk
Type Reciprocating 7 Products
7 Disk
Extended Release
Rotating
(Non-USP-NF) Drug Products
Bottle (beads)
Ointments,
Diffusion
(Non-USP-NF) Creams,
Cell(Franz) Transdermal DP

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

APPARATUS 1 (Basket Apparatus)

The assembly consists of the ff:
o Vessel (covered and made of glass and or inert transparent material)
o Motor
o Metallic dive shaft
o Cylinder Basket
VESSEL
o Partially immersed in a suitable water bath of any convenient size or heated by a suitable
devide such as heating jacket
o Water bath should maintain a temperature of 37 0.5
o The apparatus should be constant and smooth motion
o The vessel is cylindrical, hemispherical bottom and with ffg. Dimension and capacities
1L capacity = H : 160mm-210 mm, D : 98mm-106mm
2L capacity = H: 280mm- 300mm, D : 98mm-106mm
4L capacity = H: 280mm 300mm, D : 145mm-155mm
o Sides are flanged at the top
o Fitter cover is used to retard evaporation
o Shaft is positioned so that the axis is no more than 2mm at any point from the vertical axis of the
vessel and rotates smoothly and without significant wobble that could affect the result
o A speed regulating device is used which allows the rotation speed to be selected and
maintained at specified rate given in the individual monograph within 4%
o Shaft and basket components of the stirring element are fabricated of stainless steel, type 316
and other inert material
o A basket having a gold coating of about 0.0001 inch (25um) may be used. A dosage unit is
placed in a drug basket at the beginning of each test. The distance between the inside
bottom of the vessel and the bottom of the basket is maintained at 25 2mm during the test

DESIGN:
Vessel
o Made of borosilicate glass
o Semi hemispherical bottom
o Capacity : 1000ml
Shaft
o Stainless steel 316
o Rotates smoothly without significance wobble (100rpm)
Water Bath
o Maintained at 37 0.5 C

USE: TABLETS, CAPSULES< DELATED RELEASE SUPPOSITORIES, FLOATING DOSAGE FORMS

METHOD:

1. Place the stated volume of the dissolution medium (1%) in the vessel and equilibrate
dissolution medium to 37 0.5 C
2. Place 1 tab or cap in the apparatus, taking care to exclude air bubble from the surface of the
dosage form unit and immediately operate the apparatus at the rate specified (100rpm)
3. Withdraw a specimen from a zone midway between the surface of the dissolution medium and
the top of the rotating basket not less than 1 cm from the vessel wall at each time stated
o Replace aliquots withdraw for analysis w/ equal volumes of fresh dissolution medium at 37 C
4. Keep the vessel covered for the duration of the test and verify the temperature of the mixture
under test at suitable times
5. Perform the analysis as directed in individual monograph and repeat the test with additional
dosage form units
ADVANTAGES:
o Full pH change during the test
o Can be easily automated which is important for routine investigations
DISADVANTAGES:
o Basket screen is clogged with gummy particles

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

o Hydrodynamic dead zone under the basket

o Degassing is particularly important
o Mesh gets corroded by HCl solutions

APPARATUS 2 (Paddle Assembly)

DESIGN:

Vessel
o same as basket apparatus
Shaft
o the blade passes through the shaft so that the bottom of the blade fuses with bottom of the
shaft
Stirring Elements
o Made of teflon, for laboratory purpose
o Stainless steel 316
Water-bath
o Maintains at 37 0.5 C
Sintiers
o Platinum wire used to prevent tablet/capsule from floating

METHOD

1. It consists of a special coated paddle formed from a blade and a shaft that minimizes turbulence due
to stirring
2. The coated material is inert
3. The paddle is attached vertically to a variable-speed motor that rotates at a controlled speed.
4. 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
5. Most common operating speed are 50rpm for solid oral dosage forms and 25rpm for suspensions
6. A sinker such as few turns of platinum wire may be used to prevent a capsule or tablet from floating
7. Used for film coated tablet that stick to the vessel walls or to help to position tablet/ capsule under the
paddle

ADVANTAGES:
o Easy to use
o Robust
o pH change possible
o can be easily automated which is important for routine investigations
DISADVANTAGES:
o pH/ media change is often difficult
o Hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking,
floating) and therefore may significantly affect drug distribution
o Sinkers for floating dosage forms

APPARATUS 3 (Reciprocating Cylinder)

DESIGN:

Vessel
o Set of cylindrical flat bottom glass vessels
o Set of reciprocating cylinders
o Stainless steel fitting 316 and screens made of nonsorbing or non-reactive materials
Agitation type
o Reciprocating, 5-35rpm
Volume of dissolution medium
o 200-250mL
Waterbath
o 37 0.5 C

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

USE: TABLETS, BEADS, CONTROLLED AND EXTENDED RELEASE FORMULATIONS

METHOD:

1. Place the stated volume of dissolution medium in each vessel of the apparatus, assemble the
apparatus, equilibrate the dissolution medium to 37 0.5 C and remove the thermometer
2. Place one dosage form unit in each of the cylinders taking care to exclude the air bubble from the
surface of each dosage unit and immediately operate the apparatus as specified in the monograph
3. During the upward and downward stroke, the reciprocating cylinder moves through a total distance of
9.9 to 10.1cm
4. Within the time interval specified raise the cylinder 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

ADVANTAGES:
o Easy to change the pH
o pH profiles
o hydrodynamics can be directly influenced by varying the drip rate
DISADVANTAGES:
o Small volume (max. 250ml)
o Little experience and little data

APPARATUS 4 (Flow Through Cell)

DESIGN:

Reservoir
o For dissolution medium
Pump
o Forces dissolution medium through cell
o Holding a sample
o Flow rate 10-100ml/min
o Laminar flow is mainted
o Peristaltic/centrifugal pumps are not recommended
Water Bath
o Maintains at 37 0.5 C

USE: LOW SOLUBILITY DRUGS, MICROPARTICULATES, IMPLANTS, SUPPOSITORIES, CONTROLLED RELEASE

FORMULATIONS

METHOD:

1. The flow through cell is transparent and inert mounted vertically with filters
2. Standard cell diameters are 12 and 22.6 mm
3. The bottom cone usually filled with glass beads of 1mm diameter
4. Tablet holder used for positioning special dosage form (inlay tablets)
5. Place the glass beads into the cell as specified in the monograph
6. Place one dosage unit on top of the beads or on a wire
7. Assemble the filter head and fix the parts together by means of a suitable clamping device
8. Introduce by the pump of the dissolution medium warmed to 37 0.5 C through bottom of the cell to
obtain the flow rate specified and measured with an accuracy of 5%
9. Collect the eluate by fraction at each of the times stated

ADVANTAGES:
o Easy to change media pH
o pH-profile possible
o sink conditions maintained
o different modes
open system

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

closed system
DISADVANTAGES:
o DE aeration neccesary
o High volumes of media
o Labor intensive

APPARATUS 5 (Paddle over disk)

DESIGN:

Vessel
Shaft
Stirring elements
o Rotating speed 25-50rpm
Sample holder
o Disk assembly that hold a product in such a way that release surface is parallel with paddle
o Paddle is directly attached over disk assembly
o Samples are drawn between surfaces off the medium and top of the paddle blade
Volume : 900mL
Temperature : 32*C

USE: TRANSDERMAL PATCHES, OITNMENTS, FLOATERS, EMULSIONS

MODIFICATION: DISK DESIGN AND VOLUME

ADVANTAGES:
o Easy to handle
o Sink conditions are maintained
o Membrane effect is minimum
Eg. Drug is placed on a disc at the bottom
DISADVANTAGES:
o Disk assembly restricts the patch size
o Borosilicate glass
o 17 mesh is standard
o Accommodates patches up to 90 mm

METHOD:

1. The method is used for testing the release of drugs from transdermal products
2. The apparatus consists of a sample holder or disk assembly that holds the product
3. The entire preparation is placed in a dissolution flask filled with specified medium maintained at 32*C
4. The paddle is placed directly over the disc assembly
5. The disk assembly holds the system flat and is positioned such that the release surface is place parallel
with the bottom of the paddle blade. Vessel is covered to minimize evaporation during test.
6. Samples are drawn midway between the surface of dissolution medium and the top of the paddle of
specified time

APPARATUS 6 (Rotating Cylinder)

DESIGN:

Vessel
o In place of basket, cylinder is used
Shaft
o Stainless steel 36
Sample
o Mounted to cuprophan (inner porous cellulosic material) an entire system adheres to cylinder
o Dosage unit is placed in cylinder and release from side out
Water bath
o maintained at 32 0.5 C

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

USE: TRANSDERMAL PATCHES CANNOT BE CUT INTO SMALL SIZE, SOLID DOSAGE FORMS, pH PROFILE, SMALL
VOLUMES

METHOD:

1. Use the assembly from apparatus 1 except to replace the basket and shaft with a stainless steel
cylinder stirring element
2. The temperature is maintained at 32 0.5 C
3. The dosage unit is placed on the cylinder with side out
4. The dosage unit is placed to the exterior of the cylinder such that long axis of the system fits around the
circumference of the cylinder and removes trapped air bubbles
5. Place the cylinder in the apparatus and immediately rotate at the rate specified in the individual
monograph
6. Samples are drawn midway between the surface of dissolution medium and the top of the rotating
cylinder for analysis
ADVANTAGES:
o Equipment (apparatus 1) available with the manufacturers can be used with modification as
apparatus 6
DISADVANTAGES:
o Large volume of medium is required
o Drug acts diluted and causes difficulties in alaysis
o Difficult to clean the cylinder

APPARATUS 7 (Reciprocating Disk)

DESIGN:

Vessel : Flat bottom cylindrical vessel, volume of dissolution medium

Shaft
Sample: Placed on disk shape holders
Agitation : Reciprocation, reciprocating frequency 30 cycle/sec
Water bath : 37 0.5 C

USE: TRANSDERMAL PATCHES

METHOD:

1. The assembly consists of a set of volumetrically calibrated solution containers made of glass or suitable
inert material, a motor, a drive assembly used to reciprocate the system vertically
2. The samples are placed on the disk shaped holders using cuprophan supports
3. The test is carried out at 32*C
4. The reciprocating frequency is 30cycles/min

ADVANTAGES:
o Convenient method for selecting the volume of medium
o Sink conditions can be maintained
o More sensitivity
DISADVANTAGES:
o Investment in high because the design is totally different from standard equipment already
available in industry

I. ROTATING/ STATIC DISK METOD

a. Developed by late Eino nelson and described by Levi & Sahti
b. The drugs is compressed in a non-disintegrating disc without excipients
c. The disc is mounted in a holder that only one face of the disc is exposed to the dissolution
medium
d. The holder and disc are immersed in a medium and held in a fixed position as in static disc
method and rotated at a given speed in a rotating disc method

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

e. Samples are collected at predetermined times

f. Surface are of the drug through which dissolution occurs is kept constant-intrinsic dissolution
rate
II. BEAKER METHOD
a. Reported by Levy and Hayes (1960)
b. Dissolution medium, 250ml of 0.1 N HCl at 37*C placed in a 400mL beaker
c. Agitation by three blade polyethylene stirrer, 5cm diameter and rotates at 60rpm
d. Stirrer immersed to a depth of 2.7cm in medium and in the center
e. Tablets are placed in a beaker and test was carried out
f. Samples are removed and assayed for the content
III. FLASK STIRRER METHOD
a. Developed by Poole (1969), it includes RBF and a stirring element similar to that of beaker
method
b. RBF used to av89u8oid the formation of moulds of particles in different position on the flat
bottom of a beaker

CURRENT STATE FOR DISSOLUTION TEST METHODS:

Most used:

Apparatus 1 (Basket) or Apparatus 2 (Paddle)

USP equipment set-up and calibration criteria
One point acceptance criteria for immediate release
Instrument Suitability
o Choice of instrument
o Mechanical calibration (affecting hydrodynamics)
o Calibrator Tablets ( USP not EP, BP or JP)
Method development/Validation

USP Mechanical Calibration Parameters include:

Basket/Shaft wobble (No significant wobble)

Vessel/Shaft centering (2mm from centerline)
Height check / Basket Paddle Depth as measure at basket bottom or paddle bottom (252mm)
No significant vibration
Rational Speed (4%)
Vessel Temperature (37 0.5 C)
Basket Wobble (bottom rim) (1mm)

CALIBRATOR TABLETS:

1970 :
o USP Calibrator Tablets Introduced
o Disintegrating 50mg Prednisone (Upjohn)
o Non-disintegrating 300mg salicylic acid (Hoffman laroche)
1997:
o 50mg prednisone replaced with 10mg prednisone manufactured at university of Maryland
2004:
o USP begins search for replacement for 10mg prednisone tablets
USP:
o Both calibrations on a given apparatus (ie 4 calibration tests if instrument is used for paddle
and basket methods)
JP, BP, EP:
o No calibrator tablets

EVERY 6 months

10 mg prednisone tablet (LotO0C056)

o Basket: 53-57% (now 51-81%) (DPA 72.6 +/- 5.4 n=36)

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

o Paddle: 27-48% (now 26-47%) (DPA 31.7 +/- 2.0 n=24)

Salicylic Acid Tablet (Lot O)
o Basket : 23-29%
o Paddle : 17-26%

DISINTEGRATION TEST
DISINTEGRATION

This test is provided to determine whether tablets or capsules disintegrate within prescribed time when
placed in a liquid medium at the experimental conditions presented below
Compliance with the limits on disintegration stated in the individual monograph is required except
where the label states that the tablets or capsules are intended for use as troches, or are to be chewed
or are designed as extended-release dosage forms.
Determine the type of units under test from the labelling and from observation, and apply the
appropriate procedure to 6 or more dosage units
For the purposes of this test, disintegration does not imply complete solution of the unit or even of its
active constituent complete disintegration is defined as the state in which any residue of the unit,
except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or
adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core

PROCEDURE

i. UNCOATED TABLETS
a. Place 1 dosage unit in each of the six tubes of the basket and if prescribed, add a disk
b. Operate the apparatus, using water or the specified medium as the immersion fluid,
maintained at 37 2
c. At the end of the time limit specified in the monograph, life the basket from the fluid and
observe the tablets If all the tablets have disintegrated completely
d. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets. The
requirement is met if not fewer than 16 of the total 18 tablets tested are disintegrated

ii. PLAIN COATED TABLETS

a. Apply the test for uncoated tablets, operating the apparatus for the time specified in the
individual monograph.

iii. DELAYED RELEASE (ENTERIC-COATED TABLETS)

a. Place 1 tablet in each of the six tubes of the basket, and if the tablet has a soluble external sugar
coating, immerse the basket in water at room temperature for 5 minutes.
b. Operate the apparatus using simulated gastric fluid TS maintained at 37 2 as the immersion fluid
c. After 1 hr of operation in simulated gastric fluid TS, lift the basket from the fluid and observe the
tablets: the basket show no evidence of disintegration, cracking, or softening.
d. Operate the apparatus using simulated intestinal fluid TS maintained at 37 2 as the immersion fluid
for the time specified in the monograph.
e. Lift the basket from the fluid and observe the tablets: all of the tablets disintegrate completely.
f. If 1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablet, not fewer
than 16 of the total 18 tablets tested disintegrated completely

iv. BUCAL TABLETS

a. Apply the test for uncoated tablet. After 4 hours, life the bucket from the fluid and observe the
tablets: all tablets have disintegrated
b. If1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets: not fewer
than 16 of the total 18 tablets tested disintegrated completely

v. SUBLINGUAL TABLETS

DMCM
QC 2 LAB DISINTEGRATION / DISSOLUTION

a. Apply the test for uncoated tablets. At the end of the time limit specified in the individual
monograph : all of the tablets have disintegrated.

b. If1 or 2 tablets fail to disintegrate completely, repeat the test on 12 additional tablets: not fewer than
16 of the total 18 tablets tested disintegrated completely

vi. HARD GELATIN CAPSULES

a. Apply the test for uncoated tablet.

b. Attach a removable wire cloth which has a plain square weave with 1.8-2.2mm mesh apertures
and with a wire diameter of 0.60 to 0.655mm as described under the basket-rack assembly to the
surface of the upper plate of the basket-rack assembly.
c. Observe the capsules within the test limit specified in the individual monograph.
d. If1 or 2 capsules fail to disintegrate completely, repeat the test on 12 additional tablets: not fewer
than 16 of the total 18 tablets tested disintegrated completely

vii. SOFT GELATIN CAPSULES

a. Proceed as directed under hard gelatin capsules

TYPE DISINTEGRATION TIME

Uncoated
Tablets 15 minutes
Coated Tablets 30 minutes
Film-coated
other coated 60 minutes
Enteric Coated 0.1M HCl should not disintegrate
Tablets Acid in 120 mins

Mixed
Phosphate
Buffer 6.8 60 minutes

Dispersable &
Soluble Tablets within 3 minutes

Effervescent
Tablets 5 minutes

Hard Capsules

0.1M HCl should not disintegrate

Enteric Capsules Acid in 120 mins

Mixed
Phosphate
Buffer 6.8 60 minutes
Soft Capsules 60 minutes

DMCM