This document focuses on dissolution testing in pharmaceutical development, detailing the equipment, calibration processes, and the importance of in-vitro dissolution tests for assessing drug quality and performance. It covers the historical evolution of dissolution methods, guidelines for developing and validating dissolution procedures, especially for generic drug products, and emphasizes the need for rigorous testing standards and methods. The document also outlines specific considerations for dissolution testing of various dosage forms, including recommendations for media, apparatus, and acceptance criteria.

1. Presented by:
K. ARSHAD AHMED KHAN M.Pharm, (Ph.D)
Department of Pharmaceutics,
Raghavendra Institute of Pharmaceutical Education and Research [RIPER]
Anantapur.

2. CHAPTER- 4
DISSOLUTION TESTING:
1. Introduction to dissolution equipment
2. Calibration of dissolution apparatus
3. Dissolution procedure development and
validation
4. Dissolution method development for
generic drug product,

3. 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 .

4. 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

6. HISTORY of DISSOLUTION
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 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

7. 1950's-Emphasis moved from studying the effects of
physiochemical properties of drugs on dissolution to
correlation of dissolution to bioavailability of dosage
forms.
1960's- USP recognized a need for a standardized
dissolution test. The USP began experimenting with
a variety of basket and stirring devices.
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.

8. 1990 -Paddle over disk, Rotating Cylinder,
Reciprocating Disk
1995 -Reciprocating Cylinder, Flow through cell
1997 - FDA: SUPAC-MR
1997 - FDA: Guidance ER IVIVC

15. 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

16. PEEK- Poly ether ether ketone

19. SINKER (Paddle):
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

20. 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.

21. Dimensions Parameter 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 disk of which the blade is
cut out
41.5
Thickness 4.0
Positioning the stirring device 25±2

25. 16 ml
min

34. an ultra-thin dialysis membrane manufactured from
regenerated cellulose.

35. USP APPARATUS - 7

37. •The samples
are placed on
the disk shaped
holders using
cuprophan
supports
•The
reciprocating
frequency is
30cycles/min.

48. 48
Used for determining water quality
A B
Total Dissolved Gas and Oxygen Meter

49. Calibration of dissolution apparatus

56. USP Mechanical Calibration Parameters
include:
1. Basket/Shaft Wobble (No significant wobble)
2. Vessel/Shaft Centering (2 mm from centerline)
3. Height check/Basket or Paddle Depth as
measured at basket bottom or Paddle bottom
(25 + 2 mm)
4. No significant vibration
5. Rotational speed (+ 4%)
6. Vessel Temperature (37.0 + 0.5 C)
7. Basket Wobble (bottom rim) (+ 1mm)

57. Calibrator Tablets
1970’s : USP Calibrator Tablets Introduced
–Disintegrating tablet – 50 mg Prednisone
–Non Disintegrating tablet – 300 mg Salicylic Acid
1997 : 50 mg Prednisone replaced with 10 mg
Prednisone manufactured at University of
Maryland
2004 : USP begins search for replacement for 10 mg
Prednisone tablet
USP: Both apparatus Calibrate (i.e. 4 calibration tests
if instrument is used for paddle and basket
methods)
JP, BP and EP: No calibrator tablets
** Calibration done every six months

58. 58
Variability: Instrument Suitability
Set-up Parameters USP DPA
Shaft Wobble No significant
wobble
≤ 0.5 mm total
run out
Vessel/Shaft Centering 2 mm from
centerline
1 mm from
centerline
Height check/Basket or Paddle
Depth as measured at Basket or
Paddle bottom
25 + 2 mm 25 + 1 mm
Vibration as measured at center of
vessel support plate while operating
at 100 rpm/head above plate, 900
ml medium in vessels
No significant
vibration
≤ 0.1 mil
displacement
Rotational speed + 4% + 1 rpm
Basket Wobble (Bottom Rim) + 1mm ≤ 0.1mm total

59. THE DISSOLUTION PROCEDURE: DEVELOPMENT
AND VALIDATION
1. The dissolution test is required for various dosage forms
for product release testing.
2. It is also commonly used as a predictor of the in vivo
performance of a drug product.
3. To satisfy dissolution requirements, the USP provides
information in the way of a general chapter on
dissolution, as well as related chapters on disintegration
and drug release (USP 32-NF 27, 2009).
4. The USP and FDA also provide guidelines on
development and validation of dissolution procedures
(USP 32-NF 27, 2009; ICH guideline, 2005; Guidance for
Industry 1997, 2000)

60. IDEAL DISSOLUTION PROCEDURE
•The dissolution procedure requires an apparatus, a
dissolution medium, and test conditions that provide a
method that is discriminating yet sufficiently rugged and
reproducible for day-to-day operation and capable of being
transferred between laboratories.
•The procedure should be appropriately discriminating,
capable of distinguishing significant changes in a
composition or manufacturing process that might be
expected to affect in vivo performance.
•Assessing the results from multiple batches that represent
typical variability in composition and manufacturing
parameters (lubrication, blend time, compression force)
may assist in this evaluation.

61.  With regard to stability, the dissolution test should
appropriately reflect relevant changes in the drug product
over time that are caused by temperature, humidity,
photosensitivity, and other stresses.
 A properly designed test should result in data that are not
highly variable as it makes difficult to identify effects of
formulation changes.
 Dissolution results may be considered highly variable if
the relative standard deviation (RSD) is greater than 20%
at time points of 10 minutes or less and greater than 10%
RSD at later time points.
 Most dissolution results exhibit less variability than this.
The source of the variability (Formulation, Test procedure)
should be investigated and attempts should be made to
reduce variability

62. Dissolution procedure development and validation
include following conditions
• Medium-
(volume, deaeration, enzyme & IVIVC)
• Apparatus/ agitation rate-
(apparatus, sinkers & agitation)
• Study design-
(time points, observation, sampling, filters & centrifugation)
• Assay & validation-
(Specificity, linearity and range, accuracy, precessions,
robustness, solution stability, spectrophotometric
analysis & HPLC)
• Acceptance criteria.

63. 1. MEDIUM

65. Purified water is often used as the dissolution
medium.
water is inexpensive, readily available, easily
disposed of, ecologically acceptable, and suitable for
products with a release rate independent of the pH
value of the medium.
The dissolution characteristics of an oral formulation
should be evaluated in the physiologic pH range of
1.2 to 6.8.

69. In Vitro–In Vivo Correlation (IVIVC)
Bio-relevant medium is a medium that has some relevance
to the in vivo performance of the dosage unit.
Choice of a biorelevant medium is based on
1) a mechanistic approach that considers the absorption
site,
2) whether the rate-limiting step to absorption is the
dissolution or permeability of the compound

71. 2. APPARATUS/AGITATION

75. Sinkers

79. 3.STUDY DESIGN

91. DISSOLUTION METHOD DEVELOPMENT FOR
GENERIC DRUG PRODUCTS
1. In vitro dissolution testing (dissolution) plays a critical role
in the life cycle of a generic drug product.
2. In developing a dissolution test for a generic product
investigators should consider the official methods and
standards published in the USP.
3. The USP describes seven different dissolution apparatus
which can be used to develop an appropriate dissolution
method based on the drug product characteristics.

92. • The dissolution method should be sufficiently rugged
and reproducible for daily operations, capable of being
transferred between laboratories and adequately
discriminating to distinguish any changes that could
affect the product’s in vivo performance.
• The Division of Bioequivalence (DBE), in the Office of
Generic Drugs, Center for Drug Evaluation and
Research, US-FDA asks investigators to conduct
comparative dissolution testing using at least 12
dosage units each of test and reference products.

93. • Dissolution data should be generated by sampling the
dissolution medium at time points appropriate to
characterize the dissolution profile.
• It is suggested that three to four or more dissolution
time points (other than zero), equally spaced, be utilized
for rapidly dissolving drugs.
• For dissolution of extended release(ER) formulations,
more sampling time points are suggested, in order to
adequately characterize the complete dissolution profile.

94. DISSOLUTION METHOD DEVELOPMENT FOR
SOLID ORAL GENERIC DRUG PRODUCTS
One of the first step during the BE review of a potential
new generic drug product is an assessment of whether the
dissolution method proposed for the product is the
appropriate one or not.
It is recommended that the critical material attributes
(CMA) and critical process parameters (CPP) affecting the
dissolution/drug release be identified
DBE recommends following steps to select a dissolution
method for their generic product

95. Selection of dissolution
method for generic product

96.  In cases where neither a USP and nor FDA-
recommended method is available, an appropriate new
dissolution method should be developed.
 The new dissolution method development report
should be submitted to the ANDA, so that the DBE can
evaluate the feasibility of the new method.
 The new dissolution method development report
should include a pH solubility profile of the drug
substance, dissolution profiles at different rotational
speeds and dissolution media.
 Dissolution profiles should be generated using at least
three dissolution media for example, pH 1.2, 4.5, and
6.8 buffers.
 Water may also be tested as an additional dissolution
medium for method optimization.

97.  It may be difficult to achieve sink conditions for poorly
water-soluble drugs; therefore a suitable surfactant in
an appropriate concentration can be used in the
dissolution medium for these drug products.
 applicant should characterize comparative dissolution
testing using at least 12 dosage units each of test and
reference products.
 For immediate-release (IR) generic products,
dissolution testing using a single method may be
sufficient.

98. Dissolution method for an
extended-release solid oral
generic drug product

99. • The additional dissolution testing should be conducted
using at least three dissolution media, for example, pH
1.2, 4.5, and 6.8 buffers.
• Water may also be tested as a possible dissolution
medium during the method optimization process.
• If the applicant proposes to use a dissolution method
other than the USP / FDA method, then it should
submit dissolution data generated on 12 units per
strength for all strengths, for both the test (generic) and
reference products using both the USP / FDA method
and the applicants newly developed method.

100.  For delayed-release (DR) solid oral dosage forms, the
dissolution testing should demonstrate that
(a) the product is stable under the acidic conditions of the
stomach (pH 1.2); and
(b) release in the pH present in the intestine.
 If a USP method is available then dissolution should be
conducted using that method.
 If there is no USP method, then for all the strengths of a
DR product the DBE recommends that dissolution
testing should be conducted under acidic conditions (pH
1.2) for 2 h followed by neutral medium (e.g., pH 6.8).
 In general, DR products should display acid resistance
under the dissolution testing conditions.

101.  Suspensions can be considered to be similar to
disintegrated forms of solid formulations.
 Bioavailability of various poorly soluble drugs
administrated as suspension formulations has been
reported to be dissolution rate-limited.
 For dissolution testing of oral suspensions, the DBE
generally recommends the use of USP apparatus 2
(paddle) at 25 or 50 rpm.
 The in vitro testing of suspensions should be conducted
using a total of 12 units of both test product and RLD
(reference listed drug) product from 12 different
containers.
DISSOLUTION METHOD DEVELOPMENT FOR
OTHER ORAL GENERIC DRUG PRODUCTS

102. • Liquid-filled capsules can be composed of hydrophilic or
lipophilic drug substances.
• For liquid-filled capsules containing lipophilic drugs, the
DBE asks applicants to develop a “quantitative rupture”
in vitro drug release test; where, after the rupture of the
capsule shell the drug is released and measured in the
medium.
• A suitable surfactant in an appropriate concentration can
be used in the aqueous medium for these formulations.
• The use of organic solvents in the dissolution media is
not encouraged.
• For other types of formulations, applicant must provide
appropriate new validated in vitro method with strong
scientific evidence of suitability for drug product

103. • Chewing gums are sometimes used as drug delivery
dosage forms.
• Drug release from the chewing gum formulation is
complex since it is based not only on the solubilization
of the drug but also on the shear forces encountered by
the formulation.
• The USP currently does not describe a drug release test
for the chewing gum formulation.
• However, the European Pharmacopeia has published a
method for drug release testing of these formulations.
• For chewing gums, the DBE currently accepts the use of
an appropriate in vitro dissolution method using the
apparatus described in the European Pharmacopeia.

104. DISSOLUTION METHOD DEVELOPMENT FOR
NON-ORAL GENERIC DRUG PRODUCTS
• As with oral formulations, release of the API from a
non-oral formulation is the key to the performance of a
drug product.
• For non-oral dosage forms, the test is referred as “drug
release” rather than “dissolution” testing.
• For ophthalmic suspensions, generic liposome
formulations, and rectal and vaginal suppositories, if
there is no USP or FDA recommended method then the
DBE encourages the firms to develop a method to
characterize the in vitro release.

105. • For parenteral, implants, microparticles and
suspensions, if there is no USP or FDA-recommended
method then the DBE asks the firms to develop a drug
release test using USP 4 (Flow-Through Cell), or, if
applicable, apparatus 2 (paddle) or any other
appropriate method.
• Transdermal delivery systems are complex dosage
forms for which the rate and extent of the drug
release may be influenced by various parameters.
• Therefore, besides other quality control tests, quality
and reproducibility of the transdermal products
should be tested using in vitro drug release testing.
• Currently, USP describes three in vitro release testing
methods (USP apparatus 5, 6 and 7) for these
systems.

106.  Semisolid dosage forms, including creams, gels,
lotions and ointments, are generally intended for
topical route of application.
 Currently DBE does not request in vitro release
testing data in support of BE submissions to ANDAs
for the generic drug products in this category.
 In vitro release testing methods, for semisolid drug
products are done to compare performance of
certain types of pre-change and post-change
formulations.
 This can be developed using an open chamber
diffusion cell system such as a Franz cell system.

107. Generic Product specific dissolution method
development
Three Components:
1. Evaluation of the dissolution method
2. Discriminating ability of the dissolution method
3. The Acceptance criterion/criteria

108. 1. Evaluation of the dissolution method
a) Drug substance solubility profile
b) Sink condition [are recommended, NOT necessary]
c) Justification and data to support selection of surfactant
[type, concentration]
d) Dissolution data in different pH media [pH 1.0, 4.5, 6.8]
without and with [if needed] surfactant
e) Selection of an appropriate apparatus/rotation speed.
f) Selection of in vitro dissolution/release medium/media
g) Selection of an appropriate analytical method

109. 2. Discriminating ability of the dissolution
method
• Dissolution method should discriminates drug
products manufactured under target conditions vs.
formulations with meaningful variations for the most
relevant manufacturing variables (i.e., ± 10-20%
change to the specification-ranges of these variables)
• If available, submit the data showing that the selected
dissolution method is able to reject batches that are
not bioequivalent.

110. 3. Acceptance criterion/criteria
These ensure batch-to-batch consistency and to signal
potential problems with in-vivo bioavailability

111. • In future it may be useful to develop dissolution
methods using biorelevant media for formulations with
dissolution rate-limited absorption.
• it can be helpful to develop an IVIVC or even in vivo/in
vitro relationship for a new generic MR formulation.