COMPANDIAL DISSOLUTION METHOD

Prepared by,
Shivani Patel,
M.Pharm (sem-2),
Pharmaceutics.

PARUL INSTITUTE OF PHARMACY,

PARUL UNIVERSITY,
VADODARA .
 Content ….
Introduction of dissolution : Defination
Need for dissolution
USP Chapters
Compendial methodology
Compendial apparatus
Selection of media
Selection of apparatus
Validation
FDA guidelines
Optimization
Key operating parameters
Defination:-

Dissolution is a process in which a solid substance solubilizes in a

given solvent that is mass transfer from the solid surface to the
liquid phase.

It is a process by which drug released from solid dosage form and

immediately goes into molecular solution.

Dissolution rate may be defined as amount of drug substance that

goes in the solution per unit time under standard conditions of
liquid / solid interface, temperature and solvent composition.
It can be considered as a specific type of certain heterogeneous
reaction in which a mass transfer results as a net effect between
escape and deposition of solute molecules at a solid surface.
NEEDS OF DISSOLUTION TESTING

1. To ensure continuity of product quality & performance of

manufacturing process.

2. Requirement for regulatory approval for product marketing.

 Relevant USP General Chapters
 General Chapters—mandatory requirements

<701> Disintegration , <711> Dissolution , <724> Drug Release

 General Chapters—informational

<1087>Apparent Intrinsic Dissolution DissolutionTesting

Procedures for Rotating Disk and Stationary Disk

<1088>In Vitro and In Vivo Evaluation of DosageForms

<1090>Assessment of Drug Product Performance –

Bioavailability, Bioequivalence, and Dissolution

<1092>The Dissolution Procedure: Development and Validation

 Tester Equipment

Motor

Stand

Spindle

Control
Vessel
Base-Plate

Drain

DISSOLUTION 7
 COMPENDIAL DISSOLUTION METHODOLOGY

Compendial :- Reference to pharmacopoeia monograph

Compendial dissolution means dissolution of dosage form as per

USP monograph which contain all the specification and apparatus
used for it .

Compendial dissolutions apparatus are those described in USP and

are generally use for oral dosage forms .
 Discriminative Dissolution
Discriminative Dissolution is a dissolution method which is
sensitive to (formulation) variables that affect the dissolution
rate. It usually represent dissolution under test conditions
(including the selection of apparatus, media type and volume,
hydrodynamic conditions etc) that enable to discriminate between
two (or more) different formulations (e.g. which are not
bioequivalent).

However, if the dissolution discriminate between formulations

with proven bioequivalency (BE demonstrated in clinical
studies), the method is considered to be over discriminatory.

E.g., the studies are conducted when you want to evaluate whether
certain formulation changes would affect drug dissolution, and
consequently, bioperformance of a certain drug product, or when
you want to compare test to reference formulation .
OFFICIAL DOSSOLUTION MONOGRAPHS

I.P. USP B.P. E.P.

Type I paddle basket basket paddle

apparatus apparatus apparatus apparatus
Type II basket paddle paddle basket
apparatus apparatus apparatus apparatus
Type III Reciprocating flow through flow through
cylinder cell apparatus cell apparatus
Type IV flow through cell
apparatus
Type V Paddle over disk

Type VI cylinder

Type VII reciprocating

holder
USP APPARATUS d 1 (rotating basket method) :-

It consist of an 1 inch diameter and 13/8 inch high stainless steel

40 mesh wire basket rotated at speed ranging between 25-150 rpm.

It is immersed in the 900 ml of dissolution medium in a flask of

1000 ml capacity.

The medium in the flask is maintained at a constant temp of

37±0.5oC by means of a water bath the stainless steel employed for
the fabrication of basket is not totally resistant to corrosive media
like dilute acid.

Plating of gold upto 1×10-4 in thickness is permitted for use in the

acid media.
Dissolution apparatus type I

fig:Basket
 GENERAL
Media temperature 37.0 ± 0.5 °C.
Media as in monograph ± 1% (typical 900 mL);
USP states dissolved gases must not interfere.
Samples required: USP specifies 6 + 6 + 12
sequenced until specification is met.
No significant vibration.

Speed (rpm) as specified in monograph ± 4%

(100 rpm typical)

Shaft
USP: 9.4-10.1-mm diameter; 2-mm vent in drive disk.

Centering (or tilt)

USP: ± 2 mm at all points.

Eccentricity
USP: No significant wobble.

Sampling Point
USP: Midway between top
of basket and top of fluid no
closer than 1 cm to side of vessel.

Vessel
A USP: Cylindrical
with spherical bottom,
160-210 mm high, inside
diameter 98-106 mm,
glass or plastic.

Basket
(see Figure 3-7)

Basket Position
USP: 25 ± 2 mm.
Mesh size :US (40) vs. JP(around 36) 10, 20, 40 mesh

Materials :Teflon not official

Certain analytical procedures such as flurometric
determinations are sensitive to presence of nickel, chromium and
St. steel.

In such cases basket as well as bottom part of the baskets drive
shafts warrants gold plating.

This requires a 40 # screen and also 10, 20, 30 # can be used.

Usually 40# screen tends to clog and apparent rate of

dissolution is lowered.

This method is employed for dissolution testing of

suppositories and microencapsulated particles.
USP Apparatus 2 –Paddle
Vessels Same as for Apparatus 1

Stirring blade and shaft .

Metallic, or suitably inert and rigid and May be coated.

Agitation , Rotating stirrer ,Typical speeds: 50-75 rpm.

Dosage form should remain at the bottom centre of the vessel.

Sinkers used for floating dosage forms.

Drug products tested : Solid dosage forms tablets capsules

Particulates suspensions , powders.

Disadvantages : Floating dosage forms require sinker .

 GENERAL
Media temperature 37.0 ± 0.5 °C.
Media as in monograph ± 1% (typical 900 mL);
USP states dissolved gases must not interfere.
Samples required: USP 6 + 6 + 12
sequenced until specification is met.
No significant vibration.

Speed (rpm) as specified in monograph ± 4%

(50 rpm typical)

Shaft
USP: 9.4-10.1-mm diameter;
lower part polyfluorocarbon coated if desired.

Centering (or tilt)

USP: ± 2 mm at all points.

Eccentricity
USP: No significant wobble.

Sampling Point
USP: Midway between top of
blade and top of fluid; no closer
than 1 cm to side of vessel.

Vessel
A USP: Cylindrical
with spherical bottom;
160-210 mm high, inside
diameter 98-106 mm,
glass or plastic (same vessel
as specified for Apparatus 1).

Paddle
(see Figure 3-9)

Paddle Position
USP: 25 ± 2 mm.

Nonreactive helix may be

attached to floating dosage forms.
Cone formation is a typical problem for disintegrating product
sespecially if hydrophobic.

fluid interchange only at surfacecenter of cone may be saturated

solution increasing rotation speed may overcome problem .A
peak vessel with an inverted cone molded into the bottom was
developed to eliminate the potentialfor cone formation (non-
compendial).

Sinkers

A small, loose piece of nonreactive material, such as not

more than a few turns of wire helix, may be attached to
dosage units that would otherwise float

Alternative sinker devices

Advantages

Widely accepted apparatus for dissolution testing

Apparatus of first choice for solid oral dosage forms
Easy to operate
Standardized
Robust
Broad experience

Disadvantages
Fixed (limited) volume
Simulation of gastrointestinal transit
conditions not easily possible

Vessels:

Cylindrical flat-bottomed glass about 325 ml capacity

 Acceptance criteria accd to IP

S1 6 All are not < Q+5%

S2 6+6 Avg of 12 ≥ Q
And no unit is < Q-15%

S3 Avg of all 24 ≥ Q and

6+6+12 not more than 2 units
are < Q-15% and no
unit is <Q-25%
USP Apparatus 3 -Reciprocating Cylinder
USP Apparatus 3 -Reciprocating Cylinder

Reciprocating agitation Usual speed 5 to 35 dips/min

Through 10 cm vertical distance

Dosage form is placed in the cylinder

Cylinder moves horizontally to different rows of vessels

Drug products Solid dosage forms (mostly non-disintegrating)

Single units (e.g. tablets)
Multiple units (e.g. encapsulated beads)

Originally used for extended release products, particularly beads in

capsules

Generates fractionated dissolution results

Advantages

Programmable to run dissolution in different media and at

different speeds at various times

Attempt to simulate pH changes in the GI tract e.g. pH 1, pH 4.5,

pH 6.8
Disadvantages

Not suitable for dosage forms that disintegrate into small

particles
Surfactants cause foaming
Small vessel volume
Media evaporation for tests of long duration

Example: Conditions for Extended Release Testing*

USP Apparatus 4 -Flow Through Cell
Principle:-

A sample is restrained in a small volume cell and subjected to a

stream of dissolution media.

Flow through model is characterized by a vertical cylindrical cell.

The dissolution medium flows through the cell from bottom to top
of the cell, achieved by means of an external pump.

A filtration device at the top of the cell quantitatively retains all

undissolved material and provide clear solution for subsequent
assay.

Depending on whether the effluent returns to the source or not

decides the nature of the system, open or closed.
USP Apparatus 4 -Flow Through Cell

Various cell designs : 22.6 mm diameters

For special dosage forms (not harmonized)

Lipohilic solid dosage forms i.e. suppositories Powders,

granules

Flow rates
4 , 8, 16 ml/min compendial Alternative 2-32 ml/min
Operation Open system: continuous flow

Closed system: recirculate media

Media change by exchange of reservoirs Generates

fractionated dissolution results
Tablet cell Tablet cell Cell for
12 mm 22.6 mm powders
and granulates

Cell for Cell for Temperature-

implants suppositories Measuring Head
and soft
gelatin capsules
Drug products Solids: tablets, capsules, implants, powder ,
granules

Semisolids: suppositories, soft gelatin capsules, ointments

Liquids: suspensions

Disadvantages:
Limited experience with use of the apparatus –no
USP monographs
Pump precision influences the results

Advantages:

Volume of media not limited

Suitable for poorly soluble drugs
Gentle hydrodynamic conditions
Level Number tested Criteria
B1 6 Each unit is not
less than Q + 5%
B2 6 Avg. of 12 unit is
equal to or
greater than Q ,
and no unit is less
than Q- 15%
B3 12 Avg. of 24 unit ≥
Q, not more than
2 units are less
than Q- 15% and
no unit is less
than Q- 25%
USP Apparatus 5 -Paddle Over Disk

Uses paddle and vessel assembly from Apparatus 2 with the

addition of a stainless steel disk
assembly.

Temperature: 32°C

Speed: typically 50 rpm

Drug Products : Transdermal

patches.

Matrix transdermal patches can be

cut to the size of the disk assembly
Acceptance criteria
Level. value Number tested Criteria
L1 6 No individual value lies outside the
stated range
L2 6 The avg. value of 12 units lies with in
the stated range. no individual value
is outside the stated range by more
than 10% of the avg. of the stated
range
L3 12 The avg. value of 24 units lies with in
the stated range. Not more than 2 of
the 24 units are outside the stated
range by more than 10% of the
stated range; and none of the unit is
outside the stated range by more
than 20% of the avg. of the stated
range
USP Apparatus 6 –Cylinder

Uses vessel assembly from Apparatus 1 Replaces basket and

shaft with a stainless steel cylinder stirring element

Temperature: 32°C

Dosage unit is placed on the cylinder with release side out

Drug products : Reservoir transdermal patches

USP Apparatus 7 -Reciprocating Holder

Similar to Apparatus 3 but with different dimensions

Temperature: 32°C (for transdermal dosage forms)

Various devices to hold transdermal patches, tablets, capsules,

Implants.

Speed: 20-50dpm

Reciprocation through 2cm

Extended-release dosage forms
STAGES NO .OF ACCEPTANCE CRITERIA
UNIT
TESTED
L1 6
No individual value lies outside each of the stated
ranges and no individual value is less than the stated
amount at the final test time.

L2 6
The average value of the 12 units (L1 + L2) lies within
each of the stated ranges and is not less than the
stated amount at the final test time; none is more
than 10% of labeled content outside each of the
stated ranges; and none is more than 10% of labeled
content below the stated amount at the final test
time.
CONTINUE………
Extended-release dosage forms

L3 12
The average value of the 24 units (L1 + L2 + L3) lies
within each of the stated ranges, and is not less than
the stated amount at the final test time; not more than
2 of the 24 units are more than 10% of labeled content
outside each of the stated ranges; not more than 2 of
the 24 units are more than 10% of labeled content
below the stated amount at the final test time; and
none of the units is more than 20% of labeled content
outside each of the stated ranges or more than 20% of
labeled content below the stated amount at the final
test
 Immediate-release dosage forms Acceptance criteria

Stages Number of units Acceptance Criteria

tested

S1 6 Number of units tested

S2 6 Average of 12 units (S1 + S2) is equal
to or greater than Q, and no unit is
less than Q-15%.

S3 12 Average of 24 units (S1 + S2 + S3) is

equal to or greater than Q, not more
than 2 units are less than Q-15%, and
no unit is less than Q-25%.
 Delayed-release dosage forms Acid Stage -Acceptance Table

STAG NO. OF ACCEPTANCE CRITERIA

ES UNIT S
TESTED
A1 6
No individual value exceeds 10% dissolved.

A2 6
Average of 12 units (B1 + B2) is equal to or greater than Q,
and no unit is less than Q-15%.

A3 12
Average of 24 units (B1 + B2 + B3) is equal to or greater
than Q, not more than 2 units are less than Q-15%, and no
unit is less than Q-25%.
VALIDATION
History-
Concept of validation was first proposed by FDA officials in
1970, by Ted Byers & Bud Loftus.

Concept was first develop for equipment and process.

Validation is process of establishing documented evidence that

provides high degree of assurance that specific process will
consistently produce a product meeting its predetermined
specifications and quality.

Validation of Dissolution Test Apparatus

To have a high degree of assurance dissolution apparatus should
be consistence and accurate in its performance.
Therefore validation of this equipment is required.
QUALIFICATION : To ensure that equipment is fit for intended
Purpose, there are no. of qualifying steps that vendor / analyst
should apply to analytical instruments.

Equipment is evaluated through these tests & successful

completion justifies instrument operates and performs

DESIGN QUALIFICATION: When developing dissolution

method DQ is built into apparatus selection of process,

Dosage form & delivery system will determine choice of

equipment.

Example-first choice for beaded product may be USP app 3…… as

it is designed to confine beads in a screened-in cylinder.
INSTALLATION QUALIFICATION : Used to verify that
instrument has assembled in the appropriate environment & its
functioning according to predefined set of limit.

Example- Setting up fully automated dissolution testing

apparatus requires: proper plumbing, hot water source, stable
bench top.

OPERATIONAL QUALIFICATION: During this qualification

analyst or vendor assess that equipment works as specified &
generates documented data.

Example- For dissolution water bath temperature, shaft rpm speed

would be obvious operational parameters.
PERFORMANCE QUALIFICATION :This is conducted to
ensure that system is in normal operating environment &
performing designed set of tasks within the specifications.

Example-
Centering, wobble, height of paddle or basket attached to shaft,
speed, temperature
 Selection of dissolution media
• Due to the different characteristics of the novel / special
dosage forms and their sites and modes of application, it is
essential that apparatus selection ,composition of the dissolution
medium ,agitation (flow rate) and temperature be given
appropriate consideration during method design.

• For batch to batch quality testing , selection of the dissolution

medium is based , in part ,on solubility data and the dose range
of the drug product.
• Unlike compendial media (conventional buffers, USP media),
biorelevant media should represent the gastric and intestinal
environment in fasted and fed states (1, 3, 4).
•TI presence of bile, the buffer capacity, and the surface tension of
the GI fluids are taken into consideration.

•Bile salts and phospholipids may have a significant effect on the in

vivo dissolution and transport in the small intestine of poorly
soluble drug substances.

•For cases in which lipid-based formulations were characterized,

lipolysis could be accounted for by the addition of lipolytic
degradation products to the dissolution media to simulate the fed
state, because they play an important role in the solubilization
capacity of the medium .
•Duration of exposure to the various media and corresponding
flow rates should be designed to achieve a balance between the GI
fluid volumes and the physiological residence times in the GI
lumen.

•Flow rates between 4 and 8 mL/min have been proposed for

experiments that simulate fasted- and fed-state conditions.

•To develop a biorelevant dissolution test for oral dosage forms,

the physiological conditions in the gastrointestinal (GI) tract that
can affect drug dissolution should be taken into consideration
according to the properties of the drug and dosage form.
These conditions include the properties of GI fluids (composition,
volume, pH), gastric emptying (especially for nondisintegrating
systems),intestinal transit, GI motility and hydrodynamic
patterns, GI enzymes, and the presence or absence of food.

Selection of appropriate in vitro conditions (media and

hydrodynamics) that simulate the in vivo conditions can lead to
the generation of successful in vitro–in vivo correlations (IVIVC)
or in vitro–in vivo relationship (IVIVR).
 PREPARATION OF BIO RELEVANT MEDIA

Preparation of blank Fasted State Simulated Intestinal Fluid

(FaSSIF)

Dissolve 1.74 g of sodium hydroxide pellets, 19.77 g of sodium

dihydrogen phosphate monohydrate or 17.19 g of sodium
dihydrogen phosphate anhydrous and 30.93 g of sodium chloride in
5 L of purified water. Adjust the pH to exactly pH 6.5 using 1 N
Sodium hydroxide solution or 1 N Hydrochloric acid solution.
 Composition of fasted-state simulatedgastric fluid (FaSSIF).

REAGENTS QUANTITY
SOD.TAUROCHOLATE 3 mg
LECITHIN 0.75 mg
SAD.HYDROXIDE (PELLETS) 0.174 g
SOD.DIHYDROGENPHOSPHATE 1.977g
MOMOHYDRATE
SOD.CHLORIDE 3.093g
WATER 500 ml

Media has a pH of 6.50 and an osmolality of about 270 mOsmol

/kg.
Preparation of FaSSIF

DISSOLVE 3.3 g sodium taurocholate dissolved 500 mL of the

blank FaSSIF.
Then 11.8 mL of a Methylene chloride solution containing 100
mg/mL lecithin was added.
This produced an emulsion (i.e., the resulting product was turbid).
The Methylene chloride was then evaporated under vacuum using
a Rotavap at a temperature of about 40°C. About 10 min at 500
mbar foR 30 min at about 50 mbar led to complete removal of the
methylene chloride.
IT WILL result clear, micellar solution having no perceptible odor
of Methylene chloride.
After cooling to room temperature, the volume brought to 2 L
with blank FaSSIF.
 Composition of fed state simulated intestinal fluid (FaSSIF).

Reagent quantity

Sod.taurocholate 15 mg

lecithin 3.75mg

Sod.hydroxide 4.04g

Glacial acetic acid 8.65g

Sod.chloride 11.874g

water 1000ml

Media has a pH of 5.00 and an osmolality of about 6700

mOsmol/kg.
 APPLICATIONS

1. Biorelevant dissolution in pre-clinical development

2. Biorelevant dissolution in phase i clinical development

3. Biorelevant dissolution in phase ii clinical development

4. Biorelevant dissolution in phase iii clinical development

5. I - vivo in - vitro correlation (IVIVC)

 DISSOLUTION APPARATUS SELECTION
The choice of apparatus is based on knowledge of the formulation
design and practical aspect of dosage form performance in the in
vitro test system.

Apparatus for dissolution is selected according to the requirement

and dissolution study of each specific dosage form is mentioned
with required conditions .

Compendial apparatus and methods should be used at first

approach in drug development .

To avoid unneccessary proliferation of equipment and method

design , modification of compendial equipment or development
and use of alternative equipment should be considerd only when it
has been proven that compendial set up does not provide any
Meaningfull data for a given dosage form.
Sr Type of dosage Apparatus
no. form

1 Conventional Basket , paddle , reciprocating cylinder

solid oral
dosage form
2 Oral suspension paddle

3 Oral paddle
disintegration
tablets
4 Chewable Basket , paddle , reciprocating cylinder with
tablets glass beads
5 Transdermal Paddle over disk
patches
6 Topical semisolids Franz cell deffusion
system
7 suppositories Paddle , modified
basket or dual
chamber flow
through cell

8 Powders and Flow through cell

granules
9 Microparticulate Modified Flow
formulations and through cell
implants
 Method optimization

When human BA data are available from several formulations , the

dissolution test should be re-evaluated and optimized .

Goal of dissolution method optimization:

to identify in vitro test conditions that adequately discriminate critica
Formulation differences or critical manufacturing variables .

To differentiate bioequivalent batch from non bio equivalent batch

to ensure batch to batch consistency within a range that guarantees
comparable biopharmaceutical performance in vivo.
 FDA guidelines
Because of the importance of dissolution , FDA has developed
dissolution related guidances that provide information and
recommendations on the development of dissolution test
methodology , setting dissolution specifications , and the regulatory
applications of dissolution testing .

It provides information with respect to when a single point

dissolution test is adequate as a QC test and when two points or a
dissolution profile is needed to characterize the drug product.

The FDA dissolution related guidances are :

Guidance for industry : dissolution testing of immediate release

solid oral dosage form , Auguest 1997 .
Guidance for industry : extended release solid oral dosage form :
development , evaluation And application of in vitro / in vivo
correlations , september 1997 .

Guidance for industry : waiver of in vivo BA and BE for immediate

release solid oral dosage sorms based on biopharmaceutics
classification system , Auguest 2000.
 KEY OPERATING PARAMETERS
1. Media

(a)Volume : the recommended volume of dissolution medium is 500

-1000 ml , with 900 ml as the most common volume when using
the basket or paddle apparatus .

(b)Temperature : for dissolution medium it is generally 37 °C ± 05 °

C for oral dosage form and 38 ± 05 °C for suppositories and 32
± 05 °C for topical dosage forms like transedermal patches and
ointments .

(c)Deaeration : air bubbles can interefere with test result and act as a
barrier to dissolution if present on dosage form or basket mesh.

It may increase the buoyancy and lead to increase in the dissolution

rate ,or decrease the dissolution rate by decreasing surface area.
 Deaeration methods : 1) filteration
2) heating of medium
3) sonication
4) helium sparging
2. Sinkers evaluation :
Currently , the japanese pharmacopoeia is the only pharmacopoeia
that requires a specific Sinker device for all capsule formulation .

USP recommends a few turns of non reactive material wire when

dosage form tends to float.

Sinkers can significantly influence the dissolution profile of a drug.

Therefore , the use of Sinkers should be part of the dissolution

method .
 Analytical detection :

For determination of the quantitative step in the dissolution method ,

information regarding the spectral , and chemical characteristics of
the drug substance should be considered.

The quantitative methods needs to provide adequate sensitivity for

accurate determination of the analyte in the dissolution medium .

During analytical detection filteration is required to remove

undissolved drug particles from entering the analytical sample .
Sampling time point and specifications :

This parameter may change throughout a product’s development

and approval cycle are dissolution sampling time points and
dissolution limits .
If the test is used for batch to batch control ,the results should be
evaluated in regard to the established limits or specification value .

If the test is being utilized as a characterization test the results are

usally evaluated by profile comparison .

For immediate release dosage form :30-60 min test duration

single time point specification

For extended release : at least 3 test time points are chosen

 References

Pharmaceuticals dissolution testing by jennifer dressmann , indian

edition ,page no .39-45,82-86 , 357-362 .

Compendial Dissolution: Theory and Practice ,Dr. Erika Stippler

,quality standards for medicines .

Biorelevant Dissolution: Methodology and Application in

Drug Development , Qingxi Wang1, Nikoletta Fotaki2, and
Yun Mao3 , Dissolution Technologies .

Bio-relevant Dissolution Media Development Sharma MK* ,

Journal of Bioequivalence & Bioavailability .