Basic Approach to Dissolution

Methodology : Challenges and

Concerns
CONTENTS
 Theoretical aspect

 Selection of Dissolution medium

 Optimization of dissolution parameters

 Specifications /Acceptance criteria

 Comparison of Dissolution Profiling

 Biovaivers
DISSOLUTION
 In the body, a pharmaceutical
active ingredient must be “in
solution” before it can be
absorbed by the blood and
ultimately carried to the
receptor site to render a
therapeutic effect (in vivo).
 Dissolution is the process
by which that active
ingredient enters into
solvent to yield a solution.
 DISSOLUTION SOLUBILITY

Dissolution rate is defined as Absolute solubility is defined

the amount of solid substance as the maximum amount of
that goes into solution per solute dissolved in a given
unit time under standard solvent under standard
conditions of temperature, conditions of temperature ,
pH, solvent composition and pressure and pH.
constant solid surface area.

It is a dynamic process. It is a static process.

DISSOLUTION PROCESS OF SOLID
DOSAGE FORMS
NEED FOR DISSOLUTION TESTING
 Development and Optimization of dosage forms.

 Batch to batch drug release uniformity.

 Ensures quality, safety, efficacy of the product.

 Evaluation of IVIV Correlation / bioavailability .

 To support waiver for bioequivalence requirement.

 For assessing Pre and Post approval change process, or

formulations in manufacturing
Product stability, monitor formulation changes over time,
 THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM

Class 1: High Solubility – High Permeability

Class 2: Low Solubility – High Permeability
Class 3: High Solubility – Low Permeability
Class 4: Low Solubility – Low Permeability
•Highly soluble: A drug substance is considered highly soluble when the
highest strength is soluble in 250 mL or less of aqueous media within the pH
range of 1 - 6.8 at 37 ± 1°C

•Rapidly dissolving: when a mean of 85 percent or more of the labeled

amount of the drug substance dissolves within 30 minutes, using basket at
100 rpm or Paddle at 50 or 75 rpm using 500 mL media volume.

•Very Rapidly dissolving: It is similar with drug release and hydrodynamic

criteria but drug release achieved within 15 minutes

•High Permeable: A drug substance is considered to be highly permeable

when the systemic BA or the extent of absorption in humans is determined
to be 85 percent or more of an administered dose based on a mass balance
determination
Dissolution Method Goals
A successful dissolution method will be:
Discriminatory
 Robust and Rugged

Correlated to In Vivo

Transferrable

Controlled Variability

Free from artifacts

Discrimination

 Discrimination in
Dissolution simply means
being able to tell the
difference between good
and bad formulations
Development of a Discriminating
Method
The procedure should be capable of distinguishing significant
changes in composition or manufacturing process that might
be expected to affect in vivo performance.
Factors to consider:
 Qualitative and quantitative excipient changes
 Manufacturing parameters:
 Lubrication
 Blend time
 Compression force
 Drying parameters
 Steps for dissolution method
development

 Literature survey : Drug and drug product knowledge

 Selection ofApparatus
 Selection of dissolution medium
 Optimization of dissolution parameters
 Development of suitable analytical method for estimation
 Validation of analytical method
 Agitation Rate
 Should be sufficient to allow for
media to interact with dosage form
 Too much agitation can result in non-
discriminatory profiles
•Baskets – 50-150 RPM
•Paddles – 25 (Preferred for suspension)
50 RPM (preferred for BCS)
75 RPM-To eliminate coning/variability
100 RPM- for Need to justify for IR and
common for ER)
 The Ideal Dissoution Media

•Meets sink conditions

•Simple preparation
•Drug is Stable in media 24
hrs+
•Uses as little extras as
possible
–Surfactants
–Alcohol
•Biologically relevant for
site of dissolution in vivo
–IR typically in acid
–DR typically in acid, then
neutral
–MR typically in neutral
solution
 pH Depenent Solubility
 Solubility screen in multiple media (pH 1.2-7.5) should be
done to determine optimal solubility.
 If needed, use as little surfactant as necessary.
 Evaluate multiple surfactants (pay attention to grades and
vendors)
 Investigations of the stability of the drug substance should
be carried out, when needed, in the selected dissolution
medium with excipients present, at 37°c.
 Effect of pH on solubility and stability need to be evaluated.
Sink condition and Solubility
 Sink condition :Volume of medium at least three times that required in
order to form a saturated solution of drug.
 Solubility of the drug substance is usually evaluated by determining the
saturation concentration of the drug in different media at 37° using the shake-
flask solubility method (equilibrium solubility).Alternative methods for
solubility determination may also be used.
 In the absence of sink conditions, investigate methods to enhance
solubility, e.g. use of a surfactant. If a surfactant is used, its concentration
should be properly justified (e.g. typically <2% Sodium Lauryl Sulfate (SLS)).
 In certain cases, it may be necessary to evaluate the solubility of the drug at
room temperature.
 The pH of the clear supernatant should be checked to determine
whether the pH changes during the solubility test.
USP Surfactant
Use of enzymes
 The use of enzymes in the dissolution medium is permitted,
in accordance with general chapter Dissolution 711 ,when
dissolution failures occur as a result of cross-linking
with gelatin capsules or gelatin-coated products.

 A discussion of the phenomenon of cross-linking and method

development using enzymes can be found in proposed
general information chapter Capsules–Dissolution Testing and
Related Quality Attributes 1094 .
Bio-relevant Dissolution Medium
 Bio-relevant media is the media that represent the
conditions same as that of the in-vivo condition.
 The fed and fasted state may have significant effects on the
absorption or solubility of a compound.
 Composition of media that simulate the fed and fasted
condition is necessary to establish in-vivo in-vitro
correlations.
 This media reflect changes in the pH, bile concentration and
osmolarity after meal intake and therefore have a different
composition than that of typical compendial media.
Choice of bio-relevant media is usually
based upon:
 A mechanistic approach that considers the absorption site, if
known.
 Whether the rate-limiting step to absorption is the dissolution
or permeability of the compound.
 Fed and fasted states may have significant effects on the
absorption or solubility of a compound.
 These media are primarily used to establish in vitro-in vivo
correlation during formulation development and to assess potential
food effects; they are not always intended for Quality Control
purposes.
Selection of Dissolution medium
 Primary requirement for selection of dissolution media is
that, it should be able to reflect in vivo situations when it is
used to establish an IVIVC.
 For Class I and III drugs, use of simple aqueous media such as
SGF without enzymes or SIF without enzymes is
recommended.
 For Class II and III drugs, use of biorelevant media for
dissolution testing is recommended. They are: 1) SGF plus
surfactant 2) Milk with 3.5 % fat to stimulate fed state
condition 3)FaSSIF is used for poorly soluble drugs.
 Apropriate Test Duration
 Time points should be selected to adequately characterize the
ascending and plateau phases of the dissolution curve.
Typically:
 Immediate release, 85% in <15 minutes, one time point
 Immediate release, 15, 20, 30, 45, 60 minutes
 For some products, including suspensions, useful information may
be obtained from earlier points, e.g., 5–10 min.
 Delayed release,Acid 1-2 hours, Buffer +30 minutes
 Extended release, minimum of three points
– Initial (1-2 hours) to show potential dose dumping
– Intermediate point to define similar in vivo profile
– Final point to show that essentially complete release (>80%) of the
drug is achieved.
Acceptable Method Requirements
 Low variability (<20% at initial time point,
<10% at later points)
 Complete Release (85%+)
 Proper understanding of dissolution release
 Discrimination between batches -Challenged
with other formulations
 Robust/Rugged/Reproducible results
 Dissolution Acceptance Criteria
Q –Value :
Define as a percentage of drug content
dissolved in a given time period.

 It is commonly used in the USP for immediate release and

delayed release dosage forms.
 The quantity of Q is the amount of dissolved active
ingredient specified in the individual monograph
expressed as a percentage of the labeled content.
Q - Value
 For highly soluble and rapidly dissolving drug products (BCS
classes 1 and 3), a single-point dissolution test specification of NLT 85%
(Q=80%) in 60 minutes or less is sufficient as a routine quality control test for
batch-to-batch uniformity.
 For slowly dissolving or poorly water soluble drugs (BCS class 2), a
two-point dissolution specification, one at 15 minutes to include a
dissolution range (a dissolution window) and the other at a later point (30, 45,
or 60 minutes) to ensure 85% dissolution, is recommended to characterize the
quality of the product.
 For products containing water insoluble APIs, it is recommended to
have a two tire dissolution limit. For example Artemether dissolution:
NLT 40% in 1 hour and NLT 60% at the 3rd hour.
 Immediate Release Forms – Acceptance
Table USP <711>
STAGE No. of Dosage Acceptance criteria
units tested
S1 6 Each unit is ≥ Q + 5%.

S2 6 Average of 12 units (S1 + S2) is ≥Q and no

unit is < Q – 15%.

S3 12(6+6+12=24) Average of 24 units (S1 + S2 + S3) is ≥ Q,

not more than 2 units are < Q – 15% and
no single unit is less than Q – 25%.

If a sample fails either Stage S1 or S2, proceed to the next stage and test
9 the number of units indicated.
9
 Delayed Release Forms – Method A
USP <711>
 USP Delayed Release Dosage Forms – MethodA:
Media is 750 mL of 0.1N HCl
•  Samples are removed for analysis after 2 hours ± 2%
 Within 5 minutes of withdrawing the acid stage sample
aliquots, add 250 mL of 0.20-M tribasic sodium phosphate,
adjusting to pH + 0.05 at 37 °C while stirring at the
specified rate.
 Dissolution continues for 0.75 h (or per monograph) or less.
 Sample aliquots are then analyzed with Q being the
total % dissolved for both acid and buffer stages.
 Delayed Release Forms – Acid Stage
Acceptance Table USP <711>
STAGE No. of Dosage Acceptance criteria
units tested
A1 6 No individual value exceeds 10%
dissolved.
A2 6 Average of 12 units (A1 + A2) is no more
than 10% dissolved and no single unit is
greater than 25% dissolved.
A3 12(6+6+12=24) Average of 24 units (A1 +A2 +A3) is not
more than 10% dissolved and no single
unit is more than 25% dissolved.

If a sample fails either Stage A1 or A2, proceed to the next stage and test
the number of units indicated.
1
0
1
 Delayed Release Forms - Buffer Stage
Acceptance Table USP <711>
STAGE No. of Dosage Acceptance criteria
units tested
B1 6 Each unit is ≥ Q + 5%.

B2 6 Average of 12 units (B1 + B2) is ≥ Q and no unit is < Q

– 15%.

B3 12(6+6+12=24) Average of 24 units (B1 + B2 + B3) is ≥ Q, not more

than 2 units are < Q – 15% and no single unit is less than
Q – 25%.

If a sample fails either Stage B1 or B2, proceed to the next stage and test
the number of units indicated.
1
0
2
 Delayed Release Forms – Method B
USP <711>
 USP Delayed Release Dosage Forms – Method B:
 Media is 1000 mL of 0.1N HCl
•  Samples are removed for analysis after 2 hours ―
 USP Delayed Release Dosage Forms – Method B:
 Drain the acid from the original vessel and replace with
 1000mL pH6.8 phosphate buffer pre equilibrated at 37°C
or switch the dosage form to a second vessel containing the
phosphate buffer
Disssolution specification – Case
study
 Ethambutol hydrochloride 400mg [Link] applicant
claimed USP standard for the product.
 Bioequivalent of the product is accepted as per BCS class 3
based biowavier
 The applicant set the dissolution specification limits as below:
 NLT 80% (Q) in 45min at release
 NLT 75% (Q) in 45min at shelf life, which is in line with the
requirement of USP monograph.
 Is it acceptable?What limits should be applied?
Disssolution specification – Case
study -1
Answer: not acceptable
The dissolution limits at release and shelf life should be the
same.

. A limit of NLT 80% (Q) in 15min should be set for

both release and shelf life as for the BCS class 3
biowaiver.
 Why Profiling / Comparision?
 It reflects its release pattern under the selected condition sets. i.e. either
sustained release or immediate release of the formulated formulas.

 For optimizing the dosage formula by comparing the dissolution profiles

of various formulas of the same drug.

 Dissolution profile comparison between pre change and post change products
for SUPAC (scale up post approval change ) related changes or with different
strengths, helps to assure the similarity in the product performance and green
signals to bioequivalence.

 Modify formulation as per Brand Leader.

 Requirement for Comparative dissolution testing
. Two or more products or batches containing the sameAPI
are compared
. The strength of products / batches may or may not be the
same (depending on purpose of test)
. The dissolution conditions are similar, e.g.
• Apparatus, medium, volume, rotation speed & temp.
• Minimize possible experimental differences in
conditions
. Samples are taken at the same time points and the data
(dissolution profiles) compared
How to Compare?
 Aim: To show similar in vitro dissolution under physiologically
relevant experimental pH conditions.
 Advisable to investigate more than one batch of test and reference
products; must include bioequivalence batches.
 Investigate within pH 1-6.8 (normally pH 1.2, 4.5 and 6.8) and QC media
(if different).
Water may be used as an additional medium, especially when the API
is unstable in buffered media to the extent that data is unusable.
 Additional investigations may be required at pH values in which the
drug has minimum solubility.
 Use12 units to enable statistical evaluation
 For each condition, present comparative dissolution profiles(mean values
[Link]) together with statistics (max, min, mean, RSD; f2 similarity factor if
calculated; individual values)
 METHODSTO COMPARE DISSOLUTION PROFILE
Graphical method Statistical Model Dependent Model Independent
Analysis method Method

t-Test ANOVA

Zero First Hixson- Higuchi Weibull Korsemeyar Baker-

order order crowell model model and peppas Lonsdale
law model model

RatioTest PairWise Multivariate Index of Rescigno

Procedure Procedure Confidence Region
Procedure
 Guidance for Industry
A specific procedure to determine difference and similarity factors is as
follows:
1. Determine the dissolution profile of two products (12 units each) of the test
(postchange) and reference (prechange) products.
2. Using the mean dissolution values from both curves at each time interval,
calculate the difference factor (f1 ) and similarity factor (f2) using the above
equations.
3. For curves to be considered similar, f1 values should be close to 0, and f2 values
should be close to 100. Generally, f1 values up to 15 (0-15) and f2 values greater
than 50 (50-100) ensure equivalence of the two curves and thus, of the
performance of the test (postchange) and reference (prechange) products.
[Link] model independent method is most suitable for dissolution profile
comparison when three to four or more dissolution time points are
available.
The following recommendations should also be considered:

 The dissolution measurements of the test and reference batches should be

made under exactly the same conditions.
 The dissolution time points for both the profiles should be the same (e.g., 15,
30, 45, 60 minutes).
 The reference batch used should be the most recently manufactured
prechange product.
 A minimum of three points required for comparison of profile.
 Only one measurement should be considered after 85% dissolution of both the
products.
 To allow use of mean data, the percent coefficient of variation at the earlier
time points (e.g., 10 minutes) should not be more than 20%, and at other time
points should not be more than 10%.
 The mean dissolution values for R can be derived either from
(1) last prechange (reference) batch or
(2) last two or more consecutively manufactured prechange
batches.
Comparison to reference medicinal
product
 Immediate ReleaseTablets/Capsules
 > 85% dissolved within15 minutes : test and
reference similar without any further
calculation
 ≤ 85 % dissolved within15minutes: calculate f2
similarity factor

 Modified Release Preparations

 Calculate f2 similarity factor
Comparison to reference medicinal
product
Prolonged Release Preparations

 Minimum of 3 time points, but may be prudent to do more

 Particularly important if desired release profile not uniform
(e . g. immediate release outer coat and prolonged release core)
 If only3 time points: expected to mirror final specification time
points (20-30%(dose dumping),50%(defines profile),>80%)
 More time points =↑confidence of bioequivalence
e.g. for once daily preparations(1,2,4,8,12,16,20 & 24 hours)
Alternative methods to dissolution testing
In ICH Q6A permits use of disintegration testing as a surrogate
for conventional Compendial dissolution tests, provided

. highly soluble drug substances

. intrinsic rate of solubilization is rapid
. overall drug release rate is dominated by cohesive properties
of the formulation
DT in place of dissolution?
ICH Q6A decision trees #7 can be used to assess the proposed dissolution criteria,
however:
 Highly soluble throughout physiological pH range.
 Solubility at 37°C ± 0.5°C, dose + solubility < 250 ml, pH 1.2 - 6.8.

 For considering /accepting DT in place of dissolution: all the considerations

should be carefully assessed: highly soluble and very rapidly dissolving, plus
significant supporting development data – including

 when DT is more discriminating or

 has a demonstrated relationship to dissolution, robustness of the

formulation/manufacturing process have been demonstrated wrt DT, etc.

Dissolution may not be necessary or proposed as askip

test.
Example

APIs with good solubility at gastric pH levels may be

granted BCS Class I and III classification i.e. may be
characterized by disintegration testing alone.

In liquid filled capsules, drug dissolved in solubilisation aids

offering a true mechanism for drug release is likely to be the
rupture of the capsule use disintegration as a surrogate for
the QC dissolution test
Bio Waiver (In vitro equivalence
testing)
 The term biowaiver is applied to a regulatory drug approval
process where the efficacy and safety part of the dossier
(application) is approved based on evidence of equivalence other
than through in vivo equivalence testing.
 A biowaiver can be applied only for products which meet
requirements on pharmaceutical similarity, as well as similarity in
comparative dissolution tests.
 A BCS-based biowaiver has become an important and
cost-saving tool in approval of generic drugs.
 The bio-relevance of the BCS properties and the in vitro release
are best expressed through a correlation between in vitro and in
vivo data.
Requirement
 Comparative in vitro dissolution investigations should ensure that not less
than 85 % of the labeled amount is dissolved within 30 min in each
of the required media: 0.1 N HCl, pH 4.5 and 6.8 buffers. Regarding
experimental requirements, reference is made to the US Pharmacopoeia and
the US-FDA guidance for industry on DissolutionTesting of Immediate Release Solid
Oral Dosage Forms (August 1997) 3.
 Resulting profiles should be compared using the similarity factor (f2),
unless 85% or more of the labeled amount dissolves within 15 min
from both products.
 The latter case would allow the conclusion that the investigated
products are similar without requiring any further statistical
calculations.
Restrictions
BCS based waivers are not applicable for the initial in vivo
bioavailability characterization for NDAs.

Other restrictions of application include:

1) narrow therapeutic index (NTI) drug; and
2) drug products intended to be absorbed in the oral cavity.
3) Similarly, prodrugs and excipients require special consideration.
In case of prodrugs, whether to measure the prodrug or the drug
for permeability determination will depend on where the
conversion occurs.
4
 Comparison of FDA, EU and WHO
guidance on BCS based biowaiver.
Parameters US-FDA EU WHO

Allowed classes 1 1 and 3 1, 2 (weak acids), and

3
High solubility
Highest strength completely dissolved in 250mL of aqueous media at 37 ˚C ± 1 ˚C.
pH range pH 1-7.5 pH 1-6.8 pH 1.2-6.8

High permeability >90% absolute BA or >85% absolute BA or mass balance study

mass balance study
Comparison of FDA, EU and WHO
guidance on BCS based biowaiver.
Parameters FDA EU WHO

Rapid dissolution
Media (studies 900 mL or less 900 mL or less 900 mL or less
should be aqueous aqueous aqueous
conducted at 37 ± media (0.1N HCl media (pH 1.0-1.2 media (pH 1.2
1 C) or buffer, usually HCl solution; pH
SGF; pH 4.5 0.1N 4.5
buffer; and HCl or SGF; pH acetate buffer;
pH 6.8 buffer or 4.5 and pH
SIF) buffer; and pH 6.8 6.8 phosphate
buffer or SIF) buffer)
Apparatus (APP) USP APP I - 100 Paddle APP - 50 Paddle APP - 75
rpm rpm rpm
USP APP II - 50 Basket APP - 100 Basket APP - 100
rpm rpm rpm
Comparison of FDA, EU and WHO
guidance on BCS based biowaiver.
Parameters FDA EU WHO

Rapid dissolution

Criteria >85% in 30 min Class 1: >85% in Class 1: >85% in 30 min

in 3 media 30 min in 3 media in 3 media (Rapid)
(Rapid) Class 2: >85% in 30 min
Class 3: >85% in 15 in pH 6.8 medium and
min in 3 media (Very similar dissolution
Rapid); or, >85% in profile in 3 media
30 min and similar Class 3: >85% in 15 min
dissolution profile to in 3 media (Very Rapid)
RLD (Similarly Rapid)
Restrictions Narrow therapeutic drugs
Oral products intended to be absorbed in the oral cavity
Modified release drug products
 CONCLUSION:
 In vitro dissolution is the best available tool today which can at
least quantitatively assure about the biological availability of drug.

 Great Scope for New Method Development / Pharmacopoeial

monographs

 Systematic and scientific Approach is needed.

 Academic standards / Research ????? ?

 Basic infrastructure / facilities / sophisticated instrument /
positive efforts / attitude and honesty is the need of time to
improve the quality of research.
Guidelines Referred
 BCS Guidance (Waiver of InVivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System”);
August 2000
 IR Dissolution Guidance (DissolutionTesting of Immediate
Release Solid Oral Dosage Forms);August 1997
 IVIVC Guidance (Extended Release Oral Dosage Forms:
Development, Evaluation, andApplication of InVitro/InVivo
Correlations); September 1997
 General BA/BE Guidance (Bioavailability and Bioequivalence
Studies for OrallyAdministered Drug Products - General
Considerations); 2003
 WHO, US FDA and EMEA guidelines
 ICH guidelines
Thank you