Dissolution Testing and Pharmaceutical Equivalence

By
Assoc. Prof. Dr. Pornsak Sriamornsak
BSc(Pharm), RPh, MSc(Pharm), Ph.D.(Pharmaceutics)

Outline

Introduction
Biopharmaceutics Classification System
(BCS) and Bioequivalence Consideration
Tablet Evaluation
Dissolution Testing Conditions
Dissolution Profile Comparisons
Biowaivers

Introduction

Introduction

(evaluation)

(specification) (quality control)

Definition

Bioavailability :

2 Absolute bioavailability

100% Relative
bioavailability

The rate and extent to which the active drug ingredient or therapeutic moiety is
absorbed from a drug product and become available at the site of drug action

Definition

Bioequivalence :

pharmaceutical alternatives
(molar dose)

The absence of a significant difference in the rate and extent to which the active
ingredient or active moiety in pharmaceuticals equivalents or pharmaceutical
alternatives become available at the site of drug action when administered at the
same molar dose under similar conditions in an appropriately designed study

Definition

Pharmaceutical equivalent:

/
Pharmaceuticals are pharmaceutical equivalents if they contain the same amount
of the same active ingredient(s) in the same dosage form; if they meet the same
comparable standards; and if they are intended to be administered by the same
route. However, pharmaceutical equivalence does not necessarily imply
therapeutic equivalence as differences in the excipients and/or the manufacturing
process can lead to differences in product performance.

Definition

Therapeutic equivalence :

A medicinal product is therapeutically equivalent with another product if it contains
the same active substance or therapeutic moiety and, clinically, shows the same
efficacy and safety as that product, whose efficacy and safety has been
established.

Biopharmaceutics Classification System

(BCS)

A guidance for predicting the intestinal drug

absorption provided by the U.S. FDA
Used as a basis for setting in vitro dissolution
specifications
Can be also provide a basis for predicting the
likelihood of achieving a successful in vivo-in
vitro correlation (IVIVC)

Biopharmaceutics Classification System

(BCS)

Goals of the BCS Guidance:

Predict in vivo performance of drug products from in vitro

measurements of permeability and solubility

To improve the efficiency of drug development and the

review process by recommending a strategy for identifying
expendable clinical bioequivalence tests.

To recommend a class of immediate-release (IR) solid oral

dosage forms for which bioequivalence may be assessed
based on in vitro dissolution tests.

To recommend methods for classification according to

dosage form dissolution, along with the solubility and
permeability characteristics of the drug substance.

Biopharmaceutics Classification System

(BCS)
Solubility
Case 3 : High solubility Low permeability

Case 1 : High solubilityHigh permeability

-Rapid dissolution drugs

Case 4 : Low solubilityLow permeability drugs

Case 2 : Low solubilityHigh permeability drugs

Permeability

Biopharmaceutics Classification System

(BCS)

CLASS BOUNDARIES

HIGHLY SOLUBLE
the highest dose strength is soluble
in 250 ml water over a pH range of 1 to 7.5 at 37C

HIGHLY PERMEABLE
the extent of absorption in
humans is determined to be > 90% of an administered
dose, based on mass-balance or in comparison to an
intravenous reference dose.
RAPIDLY DISSOLVING 85% of the labeled amount of
drug substance dissolves within 30 minutes using USP
apparatus I or II in a volume of 900 ml buffer solutions.

Biopharmaceutics Classification System

(BCS)
Case 1 and case 3 drugs + 85% dissolution in
0.1N HCl in 15 minutes

Bioavailability of the drug is not limited by

dissolution

Biopharmaceutics Classification System

(BCS)

DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP

apparatus II (paddle) at 50 rpm.

Dissolution media (900 ml): 0.1 N HCl or

simulated gastric fluid, pH 4.5 buffer, and pH 6.8
buffer or simulated intestinal fluid.

Compare dissolution profiles of test and reference

products using a similarity factor (f2).

Quality Control for Tablets

(Raw Materials)
(In-Process)

(Granules)
(Tablets)

(Finished Products)

Quality Control for Tablets

In-process Control for Tablets

weight variation

Finished Products

weight variation, content uniformity,
amount of active ingredient, loss on drying
(bioavailability)

Tablet Evaluation
(Physical properties)

(weight variation)
(thickness)
(hardness)
(friability)
(disintegration)
(dissolution)

Tablet Evaluation
(Chemical properties)


(identification)
(uniformity of content)
(assay)
(Biological properties)

(bioavailability)
(toxicity test) (clinical test)

Weight of Tablets

Uniformity of dosage unit (USP 27)

Uniformity of weight or mass (BP)

Uniformity of dosage unit

Uniformity of dosage unit

(weight variation)
(content uniformity)

Uniformity of dosage unit

(weight variation USP27)

> 50 . > 50%
()

30

10

10
content uniformity monograph
4

Uniformity of dosage unit

10 85.0-115.0%
RSD < 6.0% (RSD = 100s / x )
1
85.0-115.0%
75.0-125.0%
RSD> 6.0% 2 20
1 30
85.0115.0% 75.0125.0% RSD 30
7.8%

Uniformity of dosage unit

(content uniformity USP27)

> 50 . > 50%

30
10

monograph

Uniformity of dosage unit

10 85.0-115.0%
RSD < 6.0%

1 85.0-115.0%
75.0-125.0%
RSD > 6.0% 2 20

1 30 85.0-115.0%
75.0-125.0%
RSD 30 7.8%

(mg)

Assay

= x 100

(mg)

800.0002

500.0232

100.0046

800.0001

500.0623

100.0125

800.0000

500.0089

100.0018

799.9998

499.6598

99.9320

799.9997

499.8963

99.9793

799.9999

615.0000

123.0000

800.0001

501.0698

100.2140

800.0000

499.8899

99.9780

800.0004

500.0023

100.0005

10

799.9998

501.0236

100.2047

Average

800.0000

511.6636

102.3327

0.0002

36.3118

7.2624

SD

RSD

= 100s / x
= (100 x 7.2624) / 102.3327
= 7.0968 (> 6.0 %)
20

(mg)

(mg)

800.0002

500.0232

100.0046

800.0001

500.0623

100.0125

800.0000

500.0089

100.0018

799.9998

499.6598

99.9320

799.9997

499.8963

99.9793

799.9999

615.0000

123.0000

800.0001

501.0698

100.2140

800.0000

499.8899

99.9780

800.0004

500.0023

100.0005

10

799.9998

501.0236

100.2047

30

799.9999

500.0060

100.0012

Average

800.0000

503.0065

100.0208

0.0002

34.6273

3.2657

SD

RSD

= 100s / x
= (100 x 3.2657) / 100.0208
= 3.2650 (< 6.0 %)

Uniformity of weight (BP)

(BP2001)

20

( )

Uniformity of weight (BP)

2

2

(mg)
BP2001
X < 80
80 < X < 250
X > 250

(%)
10
7.5
5

(%)

(mg)
800.0002

805.6789

0.5725625

820.3849

2.4108125

750.2343

6.3580125

830.1943

3.6369875

804.1243

0.3782375

802.3423

0.1554875

799.1231

0.2469125

800.0004

0.13725

10

799.9998

0.137325

0.137275

20

799.9999

801.0984

SD

19.6115

0.1373125

Uniformity of content (BP)

10
10

monograph

Uniformity of content (BP)

85.0-115.0%

1
85.0-115.0% 75.0-125.0%
20
1
30 85.0-115.0%
75.0-125.0%

1
85.0-115.0%
1 75.0-125.0%

(mg)

Assay

= x 100

(mg)

800.0002

500.0232

100.0046

800.0001

500.0623

100.0125

800.0000

500.0089

100.0018

799.9998

499.6598

99.9320

799.9997

499.8963

99.9793

799.9999

615.0000

123.0000

800.0001

501.0698

100.2140

800.0000

499.8899

99.9780

800.0004

500.0023

100.0005

10

799.9998

501.0236

100.2047

Average

800.0000

511.6636

102.3327

0.0002

36.3118

7.2624

SD

Disintegration

(solution)
(disintegration)
(dissolution)

Disintegration

USP BP

USP27

BP2001

Uncoated tablets
Plain-coated tablets
Delayed-release (enteric coated) tablets
Buccal tablets
Sublingual tablets

Uncoated tablets
Enteric-coated tablets
Effervescent tablets
Coated tablets
Soluble tablets
Dispersible tablets
Vaginal tablets

(lozenges) (chewable tablets) sustainedrelease tablets

Dissolution

(Tablet Dissolution)

Dissolution

Tablet Dissolution is a standardized method for

measuring the rate of drug release from a dosage
form. The principle function of the dissolution test
may be summarized as follows:

Optimization of therapeutic effectiveness during product

development and stability assessment.

Routine assessment of production quality to ensure

uniformity between production lots.

Dissolution

Assessment of bioequivalence, that is to say, production

of the same biological availability from discrete batches of
products from one or different manufacturers.
Prediction of in-vivo availability, i.e. bioavailability (where
applicable).

Dissolution Testing Conditions

Dissolution apparatus

Dissolution medium
Agitation
Validation

Dissolution Apparatus

apparatus 1
apparatus 2
apparatus 3
apparatus 4
apparatus 5
apparatus 6
apparatus 7

USP (/)

rotating basket
paddle
reciprocating cylinder
flow-through cell
paddle over disk
cylinder
reciprocating holder

BP (/)

rotating basket
paddle
flow-through cell

Dissolution Apparatus

USP Dissolution Apparatus 1

(Basket)

USP Dissolution Apparatus 2

(Paddle)

Dissolution Apparatus

(a)

(b)

(c)

(d)

Baskets for dissolution apparatus 1 (a) standard 40-mesh basket, (b) 20-mesh
basket, (c) 10-mesh basket and (d) suppository basket.

(a)

(b)

Paddles for dissolution apparatus 2 (a) PTFE coated paddle and (b) solid PTFE
paddle.

Dissolution Apparatus

USP Dissolution Apparatus 3

(Reciprocating Cylinder)

Dissolution Apparatus

USP Dissolution Apparatus 4 / BP Dissolution Apparatus 3

(Flow-through Cell)

Dissolution Apparatus

USP Dissolution Apparatus 5

(Paddle over Disk)

USP Dissolution Apparatus 6

(Cylinder)

Dissolution Apparatus

USP Dissolution Apparatus 7 (Reciprocating Holder)

Dissolution Medium
Carried out under physiological conditions
(370.5C) or based on physicochemical
characteristics of the drug substance and the
environmental conditions the dosage form
might be exposed
Allow interpretation with regard to in vivo
performance of the product

Dissolution Medium

Volume generally 500, 900 or 1,000 ml

Simulate gastric fluid (SGF) pH 1.2
Simulate intestinal fluid (SIF) pH 6.8 (not
exceed pH 8.0)
The need for enzymes should be evaluated
case-by-case (pepsin with SGF and
pancreatin with SIF)
Use of a surfactant is recommended for water
insoluble or sparingly soluble drug products

Agitation

Mild agitation conditions should be

maintained during dissolution testing

Basket method
Paddle method

50-100 rpm
50-75 rpm

Validation

The system suitability test using calibrators

Deaeration (if necessary)
Validation between manual and automated
procedures
Validation of a determinative step

Dissolution Profile

Standard curve
Concentration
(microgram/ml)

Abs

0.3493

10

0.6856

15

1.0229

20

1.3479

25

1.6642

Dissolution Profile
2

Abs

Standard Curve Of Paracetamol in Water(243 nm)

1.5

y = 0.0658x + 0.0264

R2 = 0.9998

0.5

Concentration (ug/ml)

0
0

10

15

20

25

30

Calculate from standard curve

Cumulative drug in whole flask

Entire drug released x 100

Entire drug in formulation

Drug in sampling
Conc x Dilution

Entire drug released

Abs

Concen
tration
(ug/ml)

Dilut
ion

Concen
tration
(ug/ml)

Sampling
3 ml
(ug/ml)

0.275

3.7781

10

37.7812

113.3435

113.3435

10

0.397

5.6322

10

56.3222

168.9666

15

0.49

7.0456

10

70.4559

30

0.754

11.0578

10

45

0.91

13.4286

60

0.959

14.1733

Time
(min)

Cumul Concen
ative in tration
3 ml
in 20 ml

Release
(ug)

%Release

755.6231

755.6231

16.1200

282.3100

1126.4438

1239.7872

26.4489

211.3678

493.6778

1409.1185

1691.4286

36.0839

110.5775

331.7325

825.4103

2211.5502

2705.2280

57.7117

10

134.2857

402.8571

1228.2675

2685.7143

3511.1246

74.9043

10

141.7325

425.1976

1653.4650

2834.6505

4062.9179

86.6759

Dissolution Profile
Dissolution Profile
120

Percent Release

100
80
60
40
20
0
0

50

100

150
Time
%Release

200

250

300

Dissolution Profile Comparisons

To ensure batch-to-batch consistency

To signal potential problems with in vivo
bioavailability
For accepting product sameness under
SUPAC-related changes
To waive bioequivalence requirements for
lower strengths of a dosage form
To support waivers for other bioequivalence
requirements

Dissolution Profile Comparisons

May be considered similar by virtue of

Over all profile similarity

Similarity at every dissolution sample time point

Dissolution Profile Comparisons

Statistical methods based in the analysis of

variance or in t-student tests

Model-independent methods

Single time point dissolution

Multiple time point dissolution
Similarity factor
Multivariate confidence region procedure

Model-dependent methods

Dissolution profile comparison

Model-independent approach using a

similarity factor

Difference factor (f1): calculates % difference

between 2 curves at each time point

Measurement of the relative error between 2 curves

n = number of time point

Rt = dissolution value of the reference batch at time t
Tt = dissolution value of the test batch at time t

Dissolution profile comparison

Model-independent approach using a

similarity factor

Similarity factor (f2): a logarithmic reciprocal

square root transformation off the sum of square
error

Measurement of the similarity in the % dissolution

between 2 curves

Model independent approach using a

similarity factor

Determine the dissolution profile of two

products (12 units each) of the test and
reference products
Using the mean dissolution values from both
the curves at each time interval, calculate f1
and f2
For curves to be considered similar

f1 = close to 0 (0-15)
f2 = greater than 50 (50-100)

Model independent approach using a

similarity factor

This model method is most suitable when 3-4 or

more dissolution time points are available
The dissolution measurements of the test and
reference batches should be made under exactly
the same conditions
Only one measurement should be considered after
85% dissolution of both the products
The percent coefficient of variation at the earlier time
point should not be more than 20% and at other
time points should not be more than 10%

Model independent multivariate

confidence region procedure

Suitable when batch variation is more than 15% CV

The following steps are suggested

Determine the similarity limits in terms of multivariate

statistical distance (MSD) based on interbatch differences
in dissolution from reference batch
Estimate the MSD between the test and reference mean
dissolution
Estimate 90% confidence interval of true MSD between
the test and reference batches
Compare upper limit of the confidence with the similarity
limit

Model dependent approaches

Select most appropriate mathematical model for the standard

batches (linear, quadratic, logistic, and Weibull models)
Using data for the profile generated for each unit, fit the data to
model
A similarity region is set based on variation of parameters of the
fitted model for test units from the standard approved batches
Calculate the MSD in model parameters between test and
reference batches
Estimate the 90% confidence region of the true difference
between the two batches
Compare the limits of the confidence region with the similarity
region

SUPAC-IR Guidance

Defines the levels of changes, recommend

tests and filling document to ensure product
quality and performance of reference with
post approval changes in

Component and composition

Site of manufacturing
The scale of manufacturing
Process and equipment changes in the
manufacturing

SUPAC-IR Guidance

Recommend dissolution profile comparisons

for approving difference level of changes and
documenting product sameness between the
test and reference product
Using a model independent approach and the
similarity factor to compare dissolution profile

IVIVC (In vitro dissolution/in vivo

bioavailability correlations)

Source : V. R. S. Uppoor . (2001), Journal of Controlled Release (72), 127132.

IVIVC (In vitro dissolution/in vivo

bioavailability correlations)

Source : V. R. S. Uppoor . (2001), Journal of Controlled Release (72), 127-132.

IVIVC (In vitro dissolution/in vivo

bioavailability correlations)

Levels of correlation

Level A
Level B
Level C
Multiple level C

Level A Correlation

Represent a point-to-point relationship

between in vitro dissolution and in vivo input
rate
Refer to a predictive mathematical model for
the relationship between the entire in vitro
dissolution time course and the entire in vivo
response time course
Linear, but nonlinear correlations are also
acceptable

Level A Correlation

Source : R. C. Rossi et al (2007), International Journal of Pharmaceutics. (Article In Press)

Level B Correlation

Predictive mathematical model for the relationship

between summary parameters that characterize the
in vitro and in vivo time courses e.g.

Mean in vitro dissolution time versus mean in vivo

dissolution time
Mean in vitro dissolution time versus mean resident time in
vivo

Not very useful because of many different

dissolution and plasma concentration profiles and
shapes can give the same mean summary
parameters

Level C Correlation

A single point relationship between a

dissolution parameter and a pharmacokinetic
parameter
Useful in early formulation development

Multiple Level C Correlation

One or several pharmacokinetic parameters

of interest to the amount of drug dissolved at
several time points of the dissolution profile
e.g.

Cmax versus %dissolved in 2, 6 and 12 hours

Biowaivers
Bioequivalence study may be replaced by
in vitro dissolution testing. When such a
substitution is allowed by registration
authorities this is referred to as a "biowaiver".

Biowaivers

Biowaivers without an IVIVC

Biowaivers based on IVIVC
Waiver of in vivo bioequivalence based on
BCS

Biowaivers without an IVIVC

New drug application of immediate-release

drug products

Clinical safety and/or efficacy studies including

data on the dose and the desirability of the higher
strength
Linear elimination kinetics over the therapeutic
dose range
The higher strength being proportionally similar to
the lower strength
The same dissolution procedures being used, and
similar result obtained in the approved medium

Biowaivers without an IVIVC

Modified-release drug products

Beaded capsules-lower strength

Tablets-lower strength

Biowaivers based on IVIVC

In vivo bioequivalence studies for extended

release products could be waived If the
sponsor has developed a correlationwhose
predictability has been evaluated
The waiver is granted if the difference in the
predicted mean CMAX and AUC between the
test and reference product is not more than
20%

Biowaivers based on IVIVC

For generic products to qualify for this

biowaiver, one of the following situations
should exist

Bioequivalece has been established for all strengths

of the reference-listed product
Dose propositionally has been established for the
reference-listed product, and all reference product
strengths are compositionally proportional or
qualitatively the same, have the same release
mechanism, and the in vitro dissolution profiles of all
strength are similar

Biowaivers based on IVIVC

Bioequivalence is established between the generic

product and the reference-listed product at the highest
and lowest strengths and for the reference-listed
product, all strengths are compositionally proportional
or qualitatively the same, have the same release
mechanism, and the in vitro dissolution profiles are
similar

Waiver of in vivo bioequivalence based on

BCS

Applicable to immediate release products

only
Not applicable to narrow therapeutic range
drugs
The drug substance should be highly soluble
and highly permeable and the drug product
should be rapidly dissolving (BCS case 1)

Waiver of in vivo bioequivalence based on

BCS

When requesting a BCS-based waiver for in vivo

BA/BE studies for IR solid oral dosage forms,
applicants should note that the following factors
can affect their request or the documentation of
their request:

Excipients
Prodrugs
Exceptions

Narrow Therapeutic Range Drugs

Products Designed to be Absorbed in the Oral Cavity

Data To Support a Request for Biowaivers

Data Supporting High Solubility

Data Supporting High Permeability
Data Supporting Rapid and Similar
Dissolution
Additional Information

The manufacturing process used to make the test product should be described
briefly to provide information on the method of manufacture (e.g., wet granulation
vs. direct compression). A list of excipients used, the amount used, and their
intended functions should be provided. Excipients used in the test product should
have been used previously in FDA-approved IR solid oral dosage forms.

European Guidance for an In Vivo

Bioavailability/Bioequivalence Waivers

If a new application concerns several

strengths of the active substance, a
bioequivalence study investigating only 1
strength may be acceptable(the choice of the
strength used should be justified on analytical,
pharmacokinetic, and safety grounds)

European Guidance for an In Vivo

Bioavailability/Bioequivalence Waivers

All of the following conditions should be fulfilled

The pharmaceutical products are manufactured by the

same manufacturer and process
The drug input has been shown to be linear over the
therapeutic dose range
The qualitative composition of the different strengths
should be the same
The ratio between amounts of active substance and
excipients is the same
The dissolution profile should be similar under identical
conditions for the additional strengths and the strength of
the batch used in the bioequivalency study

Canadian Guidance for an In Vivo

Bioavailability/Bioequivalence Waivers

Uncomplicated drug in which the proportions

of excipients to the drug and the dissolution
characteristics are the same, it is sufficient to
establish the bioavailability of one strength
For some of complicate drugs such as those
with narrow therapeutic range, steep dose
response characteristics, or nonlinear
kinetics, a single dose bioavailability study
should be conducted on each strength