Dissolution Testing in Pharmaceuticals

Contents:-
 Definition of dissolution
 Purpose and concept of dissolution testing
 History
 Dissolution testing apparatus:-
- Types
- Dimensions
 Experimental Testing conditions
 Factors affecting the dissolution test
 Dissolution Specifications

 In Vivo-In Vitro Correlations
 Validation
 Calibration Of Dissolution Test Apparatus
 Acceptance criteria
 General care and precaution

Definition of Dissolution :-
 Dissolution is defined as the process by which a
solid substance enters in the solvent to yield a
solution .
It is the process by which a solid substances
dissolves .

Purpose & Concept of Dissolution Testing
Drug absorption from a solid dosage form after oral
administration depends on the release of the drug
substance from the drug product, the dissolution or
solubilization of the drug under physiological
conditions, and the permeability across the GIT.
Because of the critical nature of the first two of these
steps, in vitro dissolution may be relevant to the
prediction of in vivo performance.

Based on this, in vitro dissolution tests are used to
(1) Assess the lot-to lot quality of drug product
(2) Guide development of new formulations
(3 ) Ensure continuing quality & performance during the
changes, such as, change in formulation,
manufacturing process, site of manufacturing etc.
So, the dissolution testing is an important tool-
1) For characterizing the biopharmaceutical quality of
product
2) For evaluation of active ingredients
3) For evaluation of possible risk such as -
Dose dumping, Food effects, Interaction with
other drugs

History:-
 It all started in 1897 with the first reference to
dissolution: Noyes and Whitney publish a paper on
"The Rate of Solution of Solid Substances in Their
Own Solution." They suggested that the dissolution
rate was controlled by a layer of saturated solution
that forms instantly around a solid particle.
 1904-Nernst and Brunner modified he Noyes-
Whitney equation by applying Fick's law of
diffusion. A relationship between the dissolution rate
and the diffusion coefficient was established.
 1930-Experiments begin with in vivo-In vitro
correlations

 1934-Switzerland's Pharmacopoeia Helvetica was the
first regulatory body to introduce a disintegration test
for tablets.
 1950's-Emphasis moved from studying the effects of
physiochemical properties of drugs on dissolution to
correlation of dissolution to bioavailability of dosage
forms.
 1950-Disintegration became an official USP Method,
USP 14.
 1960's-Although it was recognized that disintegration
was a critical process, deaggregation was essential
for bioavailability. USP recognized a need for a
standardized dissolution test. The USP began
experimenting with a variety of basket and stirring
devices.

 1960-Levy and Hayes, utilizing a beaker and a three
blade stirrer at 30-60 RPM, found significant
differences in the in vitro dissolution rates of different
brands of aspirin tablets and linked them to the
incidence of gastrointestinal irritation caused by various
brands due to their slow dissolution rates.
 1970- USP 18 incorporated the first official dissolution
test for solid dosage forms. Twelve Monographs
published in USP-NF with the official dissolution test-
a rotating basket.
 1990-Paddle over disk, Rotating Cylinder
Reciprocating Disk
 1995-Reciprocating Cylinder, Flow through cell
 1997 FDA: SUPAC-MR
 1997 FDA: Guidance ER IVIVC

Apparatus:-
 Apparatus 1 (basket):- For capsules, for dosage
forms that tend to float or that disintegrate slowly.
 Apparatus 2 (paddle):- For tablets
 Apparatus 3 (reciprocating cylinder):-For bead –
type modified-release dosage forms
 Apparatus 4 (flow cell):- For modified-release
dosage forms
 Apparatus 5 (paddle over disc) & Apparatus 6
(cylinder) :-
 For evaluating & testing transdermal dosage forms
 Apparatus 7 (reciprocating disc):- For non-
disintegrating oral modified-release & transdermal
dosage forms

Paddle Apparatus – 6 stations

Paddle Apparatus – 4 stations

Paddle apparatus Basket apparatus

Dissolution Testing in Pharmaceuticals

Calibration of Dissolution Apparatus

Dimensions of Paddle Apparatus:-Parameter Size (mm)
Vessel height 160-175
Vessel internal diameter 98-106
Paddle shaft diameter 9.4-10.1
Blade upper chord 74-75
Lower chord 42
Blade height 19±0.5
Radius of risk of which the blade is cut
out
41.5
Thickness 4.0
Positioning the stirring device 25±2

Dimensions of Basket Apparatus:-
Parameter Size (mm)
Basket shaft diameter 9.4-10.1
Screen wire diameter 0.254
Height of screen 27.0
Internal diameter of basket 20.2±1.0
External diameter of basket 22.2±1.0
Total height of basket 36.8±3.0
Openings 0.381

Experimental Testing conditions:-
 Dissolution medium – deaerated water, buffered
solution (pH- 4 to 8),dilute acid (0.001N to 0.1N HCl)
 Volume of dissolution medium - 500-1,000 ml
The quantity should be not less than 3 times that
required to form a saturated solution of the drug
substance.
 The pH of the test medium - within pH 1.0 - 6.8.
 Speed
100 rpm (for apparatus 1-basket)
50 rpm (for apparatus 2-paddle)
Temperature - 37 ± 0.5
0

Factors affecting the dissolution test:-
Related to dosage form Related to apparatus
-Polymorphism -Type of apparatus
-Particle size distribution -Dissolution media
-Solubility -pH
-Dissolution rate -Temperature
-Type of dosage form -Speed of rotation

ABSORBTION OF A DRUG AN INTACT
TABLET

Dissolution Specifications:-
Single-point specifications
 As a routine quality control test. (For highly soluble
and rapidly dissolving drug products.)
Two-point specifications
 For characterizing the quality of the drug product.
 As a routine quality control test for certain types of
drug products (e.g., slow dissolving or poorly water
soluble drug product like carbamazepine).

In Vivo-In Vitro Correlations:-
 This concept firstly arised as result of awareness of
bioavailability and in vitro dissolution rate
determinations. This term refers the establishment of
a rational relationship between a biological property
& a physicochemical property.
 The in vitro test serves as a tool to distinguish
between acceptable and unacceptable drug products.
 Acceptable products are bioequivalent, in terms of in
vivo performance, whereas unacceptable products are
not.

To achieve an in vitro-in vivo correlation, at least
three batches that differ in the in vivo as well as the in
vitro performance should be available. If the batches
show differences in in vivo performance, then in vitro
test conditions can be modified to correspond with the
in vivo data to achieve an in vitro-in vivo correlation.
 Possible reasons for poor in vivo-in vitro
correlations:-
 Study design:- Inappropriate In vivo- In vitro
test conditions.
 Dosage form:- Drug release not controlled by
the dosage form. Drug release strongly affected
by intestinal transport kinetics.
 Drug substance :- Chemical degradation in the
gastrointestinal tract. Absorption of undissolved
particles.

Validation :-
- The system suitability test using calibrators
- Deaeration, if necessary
- Validation between manual and automated
procedures
- Validation of a determinative step (i.e., analytical
methods employed in quantitative analysis of
dissolution samples).
- Validation of analytical procedure applied in
dissolution testing includes , accuracy, precision,
linearity & range.

Calibration Of Dissolution Test
Apparatus:-
- The shaft is positioned so that, its axis is NMT 2mm at
any point from the vertical axis of the vessel & rotates
smoothly & without significant wobble that could affect
the results.
- A speed regulating device is used that allows the shaft
rotation speed to be selected & maintained at the
specified rate, within ±4%.
- The distance between the inside bottom of the vessel &
the bottom of the basket (& blade also) is maintained at
25 ± 2mm during the test.

- Temperature of water bath should maintain at
37±0.5°C during the test.
- During sampling, withdraw a specimen from a
zone midway between the surface of the
dissolution medium & the top of the rotating
basket or blade, NLT 1cm from the vessel wall.
Specimens are to be withdrawn only at the stated
times within a tolerance of ±2%.

Acceptance criteria:-
Stages Number
tested
Acceptance criteria
S1 6 Each unit is NLT Q+5%
S2 6 Avg. of 12 units (S1+S2) is equal to or
greater than Q,& no unit is less than Q-
25%
S3 12 Avg. of 24 units (S1+S2 +S3) is equal
to or greater than Q, NMT 2 units are
less than Q- 15%, no unit is less than
Q-25%
 Q= amount of dissolved active ingredient
For immediate-release dosage forms :-

Stage Number
tested
Acceptance criteria
S1 6 Avg amount dissolved is NLT
Q+10%
S2 6 Avg amount dissolved (S1 + S2) is
equal to or greater than Q+5%
S3 12 Avg amount dissolved (S1 + S2
+S3) is equal to or greater than Q.
 For pooled sample:-

 For Extended-Release Dosage Forms:-
Level No.
tested
Criteria
L1 6 No individual value lies outside each of
the stated ranges & no individual value is
less than the stated amount at the final
test time
L2 6 The avg. value of 12 units ( L1+L2) lies
within each of the stated ranges, & is
NLT the stated amount at the final test
time; none is more than 10% of labeled
content outside each of the stated ranges;
& none is more than 10% of labeled
content below the stated amount at the
final test time.

 For Extended-Release Dosage Forms:-
Lev
el
No.
tested
Criteria
L3 12 The avg. value of 24 units ( L1+L2 +L3)
lies within each of the stated ranges, & is
NLT the stated amount at the final test
time; NMT 2 of the 24 units are >10% of
labeled content outside each of the stated
ranges; & NMT 2 of the 24 units are >10%
of labeled content below the stated amount
at the final test time: & none of the unit is
>20% of labeled content outside each of
the stated ranges or >20% of labeled
content below the stated amount at the
final test time.

 Acid stage
Level Number
tested
Criteria
A1 6 No individual value exceeds
10% dissolved
A2 6 Avg. of 12 units (A1+A2) is
NMT 10% dissolved , & no
individual unit is greater than
25% dissolved.
A3 12 Avg. of 24 units (A1+A2+A3) is
NMT 10% dissolved , & no
individual unit is greater than
25% dissolved.

Level Number
tested
Criteria
B1 6 Each unit is NLT Q+5%
B2 6 Avg. of 12 units (B1+B2) is
equal to or greater than Q,& no
unit is less than Q -15%
B3 12 Avg. of 24 units (B1+B2 +B3)
is equal to or greater than Q,
NMT 2 units are less than Q -
15%, no unit is less than Q -
25%
Buffer stage:-

General care and precautions:-
 Proper handling of the instrument.
 Do not start the heater if there is no water in the tank
upto the mark level.
 While filling the tank with water make sure that water
should not fall on the stirrer unit and on the heater
cover.
 Do not pull or force the paddle or basket.
 Do not over tighten the paddle

 Do not disturb the sensor tube while cleaning the
tank.
 Handle the external probe with care.
 Do not use any pointed objects for setting the
parameters.
 While paddles are rotating so first stop the paddle and
then press lift UP switch.
 MAINTENANCE / REPAIRS :-
If the instrument does not produce required
calibration results or its response is poor then it
should be labeled ˝FAULTY” and should be repaired
or serviced.

Tablet Dissolution Test in Different Stage

Dissolution Testing in Pharmaceuticals

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