Dissolution Testing

Joint UNFPA/WHO
Training Workshop on
Expert Review Panel (ERP) for RH
New Delhi, 25-26 November 2013
 Scope of Presentation
Dissolution testing
Multi-point dissolution (dissolution profile)
Comparative dissolution
Similarity of dissolution profiles
Setting of dissolution specification
BCS-based biowaiver & additional strengths
Disintegration and dissolution
Some issues:

New Delhi, November 2013

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 Immediate-release (IR) dosage
forms
IR dosage forms are preparations showing a release of the API(s)
which is not deliberately modified by a special formulation design
and/or manufacturing method (EP)
Also called Conventional-release dosage forms
Duration of the test is typically 20 to 60 minutes (USP <1092>)

The BCS introduced two specific terms

Rapidly dissolving: 85% in 30 minutes
Very rapidly dissolving: 85% in 15 minutes
In 3 BCS media (WHO BE guideline definition)

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 Dissolution conditions:
paddle and basket
Conditions should always be specified by manufacturer

Conditions Typical for Ph.Int. BCS class 1 and 3 APIs

Apparatus Paddle, 75 rpm
Dissolution medium pH 6.8 phosphate buffer
Volume of medium 500 ml (can go to 900 ml rare cases 1000 ml)
Degassed? Yes or No (degassed = mostly faster dissolution)
Temperature 37C 0.5C (fixed)
Sampling time(s) 30 minutes

Analysis Validated UV/HPLC

Requirement 80% of label claim dissolved in 30 min, etc

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 Single point dissolution test
Simplest form of dissolution
One sample is withdrawn from the dissolution medium
Through an in-line or end-of-sampling probe
filter (Ph.Int)
at a pre-determined time point and
the sample is analysed for the % API(s) dissolved
UV/VIS or HPLC most common
Result is given as e.g.
93 % in 30 minutes
No decimal is required

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 Multi-point dissolution
In multipoint dissolution
multiple ( 3) samples are withdrawn from the
dissolution medium during dissolution testing
at pre-determined time points (intervals) and
each sample is analysed for the % API dissolved

A graph of % API dissolved against time

= the dissolution profile

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 Comparative dissolution testing
The principle and basic requirements

1. The strength of products / batches may OR may not be

the same depending on purpose of test
2. The dissolution conditions must be similar, e.g.
Apparatus, medium, volume, rotation speed &
temperature
Minimize possible experimental differences in
conditions
3. Samples are taken at the same time points for data
comparison

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 Comparative dissolution testing
So when are dissolution profiles similar?
1. If both the test and reference product show
85% dissolution within 15 minutes,
the profiles are considered to be similar
No calculations are required

If this is not the case:

1. Calculate the f2 value (similarity factor):

If f2 50
the profiles are regarded similar
No decimal required (f2 = 49.51 50)

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 Comparative dissolution testing
Similarity factor f2

n = number of time points

Rt = % API dissolved of reference product at time point x
Tt = % API dissolved of test product at time point x
Minimum of 3 time points (zero excluded)
12 units (one / vessel) for each batch
Only one measurement should be considered after the reference
product has reached 85 % dissolution (or asymptote is reached)
RSD: 20% at early time point (normally at 10 mins)
& 10% at later time points

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 Typical mistakes
Often manufacturers include the following points in the f2 calculation

Time zero in the f2 calculation

% dissolved = 0 at t = 0 minutes
Points beyond the reference product reaches 85%
What is the problem with including these points?

The f2 value will increase may lead to false positive f2

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 Comparative dissolution testing
Similarity factor f2
Take note - in PQP we apply WHO requirement
Unfortunate differences between WHO, FDA and EMEA guidelines on
determination of dissolution last point for f2 calculations:

Source Only one measurement (of both products) should

be considered after:
FDA (2000) BOTH the reference AND test products have reached
85 % dissolution (or asymptote is reached)

WHO (2006) the REFERENCE product has reached 85 % dissolution

(or asymptote is reached)
EMEA (2010) ANY ONE of the reference OR test product has reached
85 % dissolution (or asymptote is reached)

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 Comparative dissolution testing
f2 calculation spread-sheet

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 Comparative dissolution testing
Dissolution conditions (study design)
Apparatus Paddle, 75 (or 50) rpm or
(choice) Basket, 100 rpm
Dissolution media 1. pH 6.8 phosphate buffer
(All three media for 2. pH 4.5 acetate buffer
full comparison) 3. Buffer pH 1.2 or 0.1 M HCl

Volume of media 900 ml or less

Temperature 37C 0.5C
Sampling points 5,10, 15, 20, 30, 45, (60, 120) min. (short intervals)
Units (vessels) 12 for official studies
For development, up-scaling, variation and biowaiver purposes

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 Comparison of products / batches

When are the dissolution properties of two products

(batches) regarded similar?

When their dissolution profiles are similar - in all three

BCS media
Statements of instability or insolubility are not
acceptable unless demonstrated / justified (literature
also acceptable)

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 Types of Biowaivers

BCS-based biowaivers (surrogate for BE studies)

Selectively applied in PQP

Additional strength biowaivers

Generally applied in PQP

NB Comparator and generic containing Class 3

APIs must both be: very rapidly dissolving (
85% in 15 minutes)

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 The BCS
High solubility definition
The highest single unit dose of an API is completely soluble in 250
ml or less of aqueous medium over the pH range 1.0 - 6.8 (at
37C)
Dose/solubility volume 250 ml (PQP Generic Guideline)
No relevance to pharmacopoeial definitions of solubility (Low
solubility in pharmacopoeia maybe high solubility by BCS
classification, since the latter is based on pH, 250ml volume
and dose)
High permeability definition (WHO, TRS937, Annex 7, 2006)
When the extent of absorption in humans is 85% based on a
mass balance determination or in comparison with an intravenous
comparator dose
Note: FDA and EU are currently 90%, WE APPLY the WHO
REQUIREMENT
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 BCS for low soluble APIs
Surfactants (about 0.25% to max. 2%) normally added to
increase solubility of BCS low soluble APIs
E.g. SLS (SDS), benzalkonium chloride, polysorbate 80
Too much surfactant may result in BCS high solubility
Then discrimination power may be lost
Solubility should be determined using different
surfactant concentrations and different surfactants
API particle size distribution specification very important

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 Disintegration vs Dissolution

Disintegration may be substituted for dissolution when

Rapidly dissolving FPPs (dissolution >80% in 15 minutes at pH 1.2,

4.5 and 6.8) and FPPs containing APIs which are highly soluble
throughout the physiological range (dose/solubility volume < 250 mL
from pH 1.2 to 6.8)

Pharmaceutical development information should be provided to

support the robustness of the formulation and manufacturing process
with respect to the selection of dissolution vs. disintegration testing

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 Some Issues
Coning (heap formation) in dissolution
vessel
Dissolution results > than assay
Filtration of dissolution samples
Chewable tablets
Suspensions for injection

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 Dissolution results above assay value
Allowable variables in dissolution test

De-aeration +1% (reduction in volume)

Volume measurement 1% (as per pharmacopoeias)
Evaporation during test +1% (as per pharmacopoeias)
Excipient interference +2% (UV, as allowed by validation)
Analytical variance * 2%
===
Total nominal +7% ??

* Validation acceptance criterion: 2 % and

Reference standard solution check: 2 %

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 Filtration of dissolution samples
1. Dissolution samples should be filtered immediately
To stop dissolution
Through in-line filter or filter at tip of sampling probe
Unless otherwise validated
2. Adsorption of the API(s) onto the filter needs to be
evaluated (validated)
Important for low dose tablets/capsules
Ideally no adsorption should occur
Discard first portion filtered (saturation of filter)

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 Chewable tablets
Chewable tablets should have
a dissolution / disintegration requirement

because they might be swallowed by a patient without proper

chewing (FDAs BA and BE studies, March 2003)
Examples:
Didanosine tablets (chewable/dispersible)
Mebendazole tablets (USP)
Chewable mebendazole tablets Ph.Int. (adopted)
The designation on the container should state that the tablets
may be chewed, swallowed whole or crushed and mixed with
food or liquid

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 Dissolution Testing for insoluble API
used in suspension for injection
For development to estimate in vitro similarity: comparison
of dissolution profile with the innovator. At least 3 media
covering the physiological range.
Demonstration of Batch-to-batch consistency at release
and for stability testing + discriminatory nature of the
dissolution method.
Use of surfactant permissible at justified levels.
Flow through cell or Apparatus II (Paddle) may be used.
More than 1 time point can be used. For modified release
(e.g. DMPA) profiles should account for possible dose
dumping.

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