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 The Pharmacist 5(1) 29-34 (2010)

Raising The Issues of Error in Dissolution Testing

Gitika Dhingra1*, Pankaj Rakha2, Rampal Rajera3 and Manju Nagpal 4

1
NCRD's Sterling Institute of Pharmacy, Nerul, Navi Mumbai- 400706, INDIA
2
Rajendra Institute of Technology and Sciences, Hisar Road, Sirsa- 125055, INDIA
3
Guru Jambheshwar University of Science and Technology, Hisar-125001, INDIA
4
Chitkara School of Pharmacy, Chitkara University, Solan- 174 103, INDIA

ABSTRACT
The effectiveness of various dosage forms relies on the drug dissolving in the fluids of the
gastrointestinal tract prior to absorption into the systemic circulation. The rate of dissolution of the tablet
or capsule is therefore crucial. So invitro dissolution test is comprehensively defined and given a status of
official test in the various Pharmacopoeias. The dissolution test not only provides information regarding
the rate and extent of drug absorption in the body, it also assesses the effects of drug substance
biopharmaceutical properties and formulation principles on the release properties of a drug product.
Nevertheless, despite the wide use of dissolution testing by the pharmaceutical industry and regulatory
agencies, the fundamentals and utilities of dissolution testing are still not fully understood. The objective of
this article is to provide a concise review of various factors that may lead to erroneous results in dissolution
test, highlight issues regarding existing dissolution methods, and review challenges of improving some of
these current dissolution methods, particularly those used for assessing invivo drug product performance.

Key Words: invitro dissolution test, vibration, calibration, deaeration, multipoint sampling.

INTRODUCTION
During past few years, the field of dissolution
testing has expanded considerably to address not only the
questions of quality control of dosage forms but additionally
to play an important role in screening formulations and in
the evolving bioequivalence paradigm. Dissolution tests are
used now a days in the pharmaceutical industry in a wide
variety of applications: to help identify whether
formulations will produce the best results in the clinic, to
release products to market, to identify batch-to-batch
reproducibility, and to help identify whether changes made
to formulations or their manufacturing procedure after
marketing approval are likely to affect the performance in
the clinic (1). Further, dissolution tests can sometimes be
implemented to help determine whether a generic version of
medicine can be approved or not.
As reliance on the dissolution test as a predictor of
continued bioavailability and bioequivalence increases, the
test conditions have come under increasing scrutiny. It has
been found that the result of dissolution test (dissolution
rate) is affected by various factors like hydrodynamic
aspects of fluid flow in the vessel, vibrations, mesh size of
basket etc. Considering the importance of invitro test in
mimicking the invivo performance of drug product, it is
mandatory to consider such parameters. The working
conditions of the equipment are of great importance. In this
review, an attempt has been made to discuss various sources
of error while performing dissolution test and using
dissolution equipment.
The source of deviation from accurate results in
29
dissolution test can be broadly classified into following
categories:
A. Equipment Related Factors
B. Process Related Factors
C. Drug Substance Properties Related Factors
D. Drug Product Properties Related Factors
E. Miscellaneous Factors
A. Equipment Related Factors
Dissolution equipment is a machine. The initial
quality of the device and its subsequent care and
maintenance will influence both operational reliability and
product dissolution rate results. A discussion of the
dissolution equipment is important as the dissolution rate is
generated by the stirring mechanism interacting with the
dosage form in the media. The environment in which it
operates will affect performance, and it needs to be running
properly at all times (2). Some of the parameters associated
with equipment, leading to errors in result are discussed
below:
1. Dissolution Test Vessel
2. Paddle/ Basket Shaft
3. Vibrations
4. Use of Filters
5. Calibration of Dissolution Vessel
1. Dissolution Test Vessel: Dissolution testing is an attempt
to create a perfectly controlled space, with a
hydrodynamically consistent environment. “Ideally the
 30
upper portion of each vessel would be perfectly cylindrical,
and its bottom would be a perfect hemisphere. They are
made one at time by manually blowing a molten mass of
glass into a mold. As a result, the vessels are not uniform
with respect to weight, height, cylindrical shape,
hemispherical curvature, and inner diameter. The inside
surface of each should be inspected for abnormalities.”(3)
This statement appeared in the 1978 Guidelines for
Dissolution Testing, shortly after dissolution was added to
the USP. The recognized variability led to the creation of
USP specifications for dissolution vessels. But these
specifications only defined the inner diameter and the
height (4).
Various attempts have been made to study the
variables associated with vessel dimensions that affect the
dissolution rate. Some have concluded that a major source
of dissolution result variability appears to be the geometric
parameters of the dissolution vessel and stirring mechanism
(5,6)
. In one such study, the effect of the irregular inner shape
of a glass vessel on drug dissolution results was
investigated. The inner shapes of commercially available
glass vessels obtained from three different manufacturers
were examined for unevenness of the inner surface of the
vessel and for distortion of the inner shape as a whole using
a three-dimensional coordinate measuring machine. A
precision vessel (Takao, Japan) was manufactured by a new
glass processing technology and displayed an almost ideal
inner shape consisting of a cylinder and hemisphere. In
contrast, two conventional vessels, vessel A (manufacturer
A, Japan) and vessel B (manufacturer B, USA), exhibited
distortion and unevenness in various places. The vessel
bottoms in particular deviated from the ideal hemispherical
shape, and curvature among vessels differed widely. The
inside of the cylinder of these two manufacturers' vessels
also deviated from the ideal circular shape. The dissolution
results of USP Prednisone Calibrator tablets were compared
for the precision vessel and vessel A. Variability in test
results was markedly lower when the precision vessel was
used. For vessel A, however, test results varied widely
between vessels used and between positions in the
dissolution tester. In addition, the mean values of
prednisone dissolution percentages obtained from six
positions differed significantly (p < 0.05) among vessels.
These results suggest that the shape of a glass vessel is
critical to obtaining unvarying and reproducible dissolution
test results (7).
Other studies have shown high variability within
the vessel flow when using Apparatus 2.This can result in
extreme variation in flow dynamics along the hemispherical
surface(8). By the mid 1980's specifications were
established, but were later extended to include taller vessels
(9)
. One assumption made in these specifications is that the
cylinder and hemisphere of the vessel is perfectly uniform
with only the height and width needing measurement. Since
the glass vessels are individually made, the vessel will
always fall short of perfection, both in the cylinder and the
hemisphere.
Dhingra et al
The reality is that there are no perfect geometric shapes in
the real world; they only exist in the mathematical
definitions. Everything is an approximation of the ideal. The
question is how far off can we be? While the individual
dosage form will demonstrate the greatest variability, the
desire is to understand and remove dissolution apparatus
biases. Some vessel variability may have little impact on
certain dosage forms, but it has been shown that some
individual vessels will statistically yield higher or lower
results (4).
2. Paddle/ Basket Shaft: Close inspection of USP apparatus
I & II before use can help identify sources of error. In both
cases, shafts must be straight and true. The paddles are
sometimes partially coated with Teflon. This coating can
peel and partially shed from paddle, causing flow
disturbance of hydrodynamics within the vessel. Paddles
can rust and become nicked and dented; this can adversely
affect dissolution hydrodynamics and be a source of
contamination (1).
Two types of basket shafts are commercially
available to the analyst. One type has an O-ring inset in the
disk at the end of the shaft with the basket fitting snuggly
around the O-ring. The other has three clips attached to the
disk at the end of the shaft (10). The basket is attached by
fitting between the clips and the disk. The latter design is
described in USP 24 General Chapter on Dissolution <711>
(11)
. These two types of basket shafts were compared using the
two USP Calibrator Tablets, Prednisone and Salicylic acid,
and three development products. There was no difference
between the two basket shaft types for the three
development products and USP Salicylic Acid Tablets.
However, the USP Prednisone Calibrator Tablets did show a
significantly different dissolution rate. The difference
showed a higher dissolution rate using the clipped basket
shaft design. The clipped basket shaft is the official USP
design; however there are some drawbacks to this design.
The clips protrude and disturb the fluid flow in the vessel.
The clips can weaken over time and cause the basket to be
attached too loosely to the shaft thereby increasing the
chance for wobble. Hence baskets need special care and
examination. Later on they can become frayed, misshapen
or warped with use. Screen mesh size may change over time,
especially when used with acidic medium. Baskets are
especially prone to gelatin or excipient build up if not
cleaned immediately after use (1).
3. Vibrations: Vibration is a complicated concept that can
result in the addition of energy to a system. The addition of
energy from an external source can alter the results of a
dissolution evaluation. Such an alteration is an unacceptable
source of error that must be minimized. As far as USP is
concerned it has been noted that there is brief mention of
vibrations requirements consisting of statement that "No
part of the assembly, including the environment in which the
assembly is placed, contributes significant motion,
agitation, or vibration beyond that due to the smoothly
rotating stirring element" (12).
 Raising The Issues of Error in Dissolution Testing
Reports of the adverse effects of vibration have
appeared in the literature as early as 1971, when Beyer and
Smith reported a sixfold increase in the dissolution rate of
tolbutamide tablets using a basket method. This increase
was observed when the measured displacement was
increased from 0.05 mil to 0.8 mil (1mil=0.001inch) (13).
However, the frequency of this displacement was not
reported. Hanson reported a similar effect for salicylic acid
calibrators in apparatus 1, and recommended that the
horizontal displacement should be kept below 0.1 mil when
the frequency is in the range of 50 to 60 Hz (14).
Vibrations can be minimized by eliminating all external
sources so that only the tester machinery is left as a potential
vibration source that is external to the drug delivery system
under evaluation(15).
Vibration sources can be very diverse in origin.
Some of the sources are internal sources, external sources,
and intermittent and operational sources. The Internal
Sources includes vibrations includes the
Heater/Circulator, the Drive Motor, the Drive Belts, the
Bearings etc. External Sources means environment
directly around the instrument. Almost no attention is paid to
environmental sources of vibration. For example, pumps,
refrigerators etc. kept on the same slab cause vibrations.
Only on some rare occasions there is such an influence that
the lab is more or less forced to concede that there have been
hidden forces at work. The trouble with any intermittent
problem is that it may not always be there. The best example
is the slamming door. Portable A/C units can also be a
problem. Intermittent sources can also be operator-
generated. Some instruments have electric-head drives (to
raise and lower the head), and some are manually operated,
either with a pneumatically assisted swing head or with a
guided vertical drop. Both of these mechanisms can be
sources of problems if not smoothly placed into the
operating position. This, again, is particularly the case with
USP Apparatus 1 baskets. Sudden movements during the
disintegration of the Prednisone Tablet can fire a shower of
tablet material out of the basket and into the medium. A
failed test is not far off (16).
4. Use of Filters: Most current dissolution procedures
require samples to be withdrawn from the vessel, the
exception being when the concentration is determined in
situ with fiber optics. No matter whether the sample is
withdrawn manually or automatically, effective filters are
necessary to prepare the sample for analysis; otherwise,
undissolved material from the medium could influence the
results. All of the filter materials available on the market for
dissolution testing may not be equally suitable for this task.
For example, it is important that filter materials should have
little or no tendency to adsorb the drug, since adsorption to
the filter will result in out-of-specification results (17).
5. Calibration of Dissolution Apparatus: It is simply a
demonstration of suitability for use in that test and, in
concept, is similar to system suitability determinations for
other analytical procedures. The process by which a test
apparatus is determined to meet the compendial
31
(dimensional and operational) specifications has been
termed mechanical calibration, while the use of reference
standard tablets is given the designation chemical
calibration. Chemical calibration allows a final and
summative confirmation of the suitable operation of the
integrated dissolution assembly, beyond the evaluation of its
separate component attributes (e.g., stirring element
dimensions, control of rotation speed, dissolution medium
volume). It challenges the test assembly to perform its
designed function as a sample preparation system (18). But
literature shows the cases of multiple failures worldwide
for chemical calibration of dissolution baths using the two
performance verification standards (earlier known as
calibrator tablets), the disintegrating Prednisone RS
(reference standard) tablets, and the non-disintegrating
Salicylic Acid RS tablets. Dissolution of Prednisone RS
tablets is very sensitive to the degree of dissolved gasses in
the medium. Calibration using these RS tablets requires
expertise and is very time consuming. Failure is very
common for first time analysts, and this adds to the
frustration. Several other parameters, such as the method of
tablet introduction, size and type of sampling probes, also
add to the variability of the results during the calibration. As
a result of these problems, the benefits of chemical
calibration are now being questioned by the pharmaceutical
industry. Performance verification standards are supposed to
be reliable, reproducible, and easy to use. Unfortunately, the
existing calibrator tablets have failed to meet these minimum
requirements for the end-users (19). Mechanical calibration,
on the other hand, is a simpler alternative. But alone it is not
sufficient to adequately furnish a robust demonstration of
system suitability (18).
B. Process Related Factors
The dissolution test should not be considered as
absolute analytical procedure. It is always comparative,
whether as a bioequivalence test assessing different
formulations, as a stability test comparing stored products
with the original one, or as a quality control test comparing
different batches against previously established limits. As a
comparative test procedure, the consistency and
reproducibly of both the analytical equipment itself and the
techniques used are essential. Over the years many different
apparatus have been developed but a limited number of
standardized procedures are now used with only minor
differences used throughout the world (20). These procedures
are documented in major pharmacopoeias. Various factors
associated with dissolution test procedure that may lead to
errors:
1. Use of water as dissolution media
2. Sample introduction
3. Single point Vs multiple point sampling
4. Deaeration of media
5. Controlled release dosage forms
1. Use of Water as Dissolution Media: Many compendial
dissolution tests specify water as the dissolution medium.
When dissolution procedures were first being added to the
 Dhingra et al
32
monographs, the default "First Case" was usually specified.
This consisted of 900 mL of water as dissolution medium
with USP Apparatus 1 (Basket Method) at 100 rpm, or later,
USP Apparatus 2 (Paddle Method) at 50 rpm. Products not
meeting the "First Case" tolerance specification of NLT
75% "Q" in 45 minutes using this method was asked to
submit data for a new procedure.
Water lacks buffering capacity and thus, in some
instances, the pH of the medium may change as the drug
dissolves (as in the case of salts) (21). Also, because water is
not representative of the gastrointestinal environment, it is
not considered a physiologically relevant medium.
Sometimes it is questioned whether dissolution tests can
predict in vivo dissolution and absorption when the in vitro
test conditions do not well simulate the physiological
environment of the gastrointestinal tract.
FDA has undertaken a study to evaluate simple, alternative
dissolution media that can serve as a quality control test, for
products currently having water as the media. Several FDA
field laboratories were involved in the undertaking. Samples
of the innovator (brand name) drug product along with FDA
approved generic products were collected and screened for
release profile performance in media of various pH values
(e.g., pH 1.2, 4.5, and 6.8). Dissolution aliquots were taken
at 15, 30, 45 and 60 minutes, and the profiles are assayed in
each alternative test medium and compared to the profiles
generated using water. A medium having comparable or
better performance than the water medium was selected for
the final testing, in which the collected products were tested
using the new medium versus the USP-specified water
medium. The data were then reviewed and a final
recommendation forwarded to the USP for consideration as
a compendial monograph requirement. All products
performed at least as well in the alternative media as they did
in water. For some products, it was recommended to USP
that the tolerance should be increased based on the
dissolution results obtained in the alternative medium.
In conclusion, using a dissolution medium that better
simulates the environment of the gastrointestinal tract will
help make dissolution testing conditions more
physiologically relevant to in vivo absorption and useful in
evaluating the quality and stability of these drug products (22).
2. Sample Introduction: Sample introduction can be tricky
and unfortunately at times, not easy to perform
reproducibly. Products can have a dissolution rate that is
“position dependent”. For example, if the tablet is off-
center, the dissolution rate is high due to shear forces or if it
is in the centre, coning may occur and dissolution rate will
go down. Film coated tablets can be sticky and pose
problems related to tablet position in the vessel.
Suspensions can be introduced in a variety of ways. Some
examples are to manually use syringes or pipettes, pour from
tared beaker, or automate delivery using calibrated pipettes.
Each method has its own set of limitations. Mixing of the
sample will generate air bubbles; therefore, the mixing time
of suspension samples must be strictly uniform to reduce
biased results (1).
3. Single Point Vs Multiple Point Sampling: A seemingly
robust and discriminating method can present unexpected
results based on the number of sampling time points and
sample withdrawals. In one study that included BCS Class II
drug product, it was determined that multiple sample pulls
from the dissolution vessel, as in a “profile” experiment
(typically used in the R&D or stability testing
environments) versus a single-pull (typically used in the QC
environment), resulted in different dissolution rates(23). It is
believed that this discrepancy is a result of a greater
disturbance of the fluid hydrodynamics in the dissolution
vessel caused by the additional insertions and residence of
the sampling probe in the vessel during multi-point
sampling. This may be due to hydrodynamic effects that can
potentially influence in vitro dissolution results. When
developing a discriminating and robust dissolution method,
one should evaluate how the method will ultimately be
implemented in the manufacturing environment. Additional
examples in the literature suggest that the hydrodynamic
conditions, drug release pattern, or mechanical forces of an
in vitro dissolution are crucial to the drug release rate (24, 25). In
the case of the dissolution method, the impact of the
sampling technique on fluid hydrodynamics and the
subsequent effect on method robustness should not be
overlooked. Use of single-point versus multi-point profile
testing should be taken into account early in the method
development process.
One cause of inaccurate results may be that too
great a volume of medium has been removed, through
multiple sampling without replacement, in which case sink
conditions may no longer prevail1.
4. Deaeration of Media: The level of dissolved gases is
related to the presence of bubbles. Bubbles are common and
will cause problems in non-deaerated medium. In <711>, it
is stated that bubbles can interfere with dissolution test
results and should be avoided. Dissolved air can slow down
dissolution by creating a barrier; either adhering to tablet
surface or to basket screens or particles can cling to bubbles
on the glass surface of the vessel or shafts (1).
Many methods have been described for the
deaeration of dissolution media, as required by the USP as
well as worldwide regulatory agencies. The USP General
Chapter Dissolution <711> suggests heated vacuum
filtration as one method of deaeration. In a study, this
method of deaeration, with 1L of water produced media with
2.8 mg/L dissolved oxygen remaining. Helium sparging ais
another method of deaeration achieved lower levels of
dissolved oxygen. Helium sparging produced media
deaerated to the same level as the USP vacuum filtration
technique if the media was sparged at a flow rate of 40 mL/s
for approximately 0.5 minutes per liter of media container
volume. This recommendation was based on the fact that
partially filled containers of dissolution media did not
deaerate as efficiently as full ones (26).
5. Controlled Release Dosage Forms: Although
dissolution tests have been successfully implemented on
 Raising The Issues of Error in Dissolution Testing
conventional dosage forms, there are enormous difficulties
in establishing proper dissolution test conditions and
parameters for testing sustained or controlled release oral
dosage forms because of prolonged gastrointestinal
residence of the dosage form and variabilities in
physiological conditions of the gastrointestinal tract.
Formal guidelines to evaluate sustained or controlled
release products do not exist. The current trend is to evaluate
each and every sustained or controlled release dosage form
on individual basis. The formulation scientists and
regulatory authorities face an enormous challenge of
generalising the test conditions for dissolution testing
because most individual drug candidates for sustained or
controlled release dosage forms and their delivery design
possess diverse physicochemical and pharmacokinetic
properties requiring specific considerations. The difficulties
are also in simulating in vivo conditions in invitro. Since
most sustained or controlled release preparations are
designed for prolonged release and therapeutic effect,
variabilities in invivo conditions (such as presence and
nature of food in the gastrointestinal tract, time of the day the
dosage form is administered) which can substantially affect
the release profile of the drug are bound to happen(27).
6. Automation: While automation of dissolution sampling
is very convenient and laborsaving, errors often occur with
these devices because the analysts tend to overlook problem
area. Sample lines are often a source of error for a number of
reasons: unequal lengths, crimping, wear beyond limits,
disconnection, carry-over, mix-ups or crossing and
inadequate cleaning. Pumping tubes may wear out through
normal use or repeated organic solvent rinsing and may
necessitate replacement1.
C. Drug Substance Properties Related Factors
Knowledge of drug properties like solubility of drug, effect
of pH change, crystalline structure is important. One could
anticipate precipitation of the drug as the pH changes in
solution, or if release from the dosage form leads to
supersaturation of the test media e.g. preparation of a
standard solution may is an important step. It is customary to
use a small amount of alcohol to dissolve the standard
completely. A history of the typical absorptivity range of the
standard can be very useful to determine if the standard has
been prepared properly (1).
D. Drug Product Properties Related Factors
Dissolution profile may help in identifying trends and
effects of formulation changes. When the results are highly
REFERENCES
1) Dressman JB, Kramer J. Pharmaceutical Dissolution
Testing. Taylor and Francis Group,
New York; 2005.
2) Gray V. Challenges to the Dissolution Test, including
Equipment Calibration. Dissolution Technologies
2006; 13(2) 6-8.
3) Cox D, Douglas C, Furman W, Kirchhoefer R,
Myrick J and Wells C. Guidelines for Dissolution
33
variable, it indicates that the method is not robust. Two
major casual factors influence variability: Mechanical and
Formulation.
· Mechanical causes can arise from the dissolution
conditions chosen. An apparatus or speed change
may change the results.
· The formulation can have poor content uniformity,
additionally, reactions and/ or degradation may be
occurring in situ. The film coating may cause
sticking to the vessel walls. Upon aging, capsule
shells are known for the pellicle formation and
tablets may become harder or softer, depending upon
the excipients and drug interaction with moisture,
which in turn may affect the dissolution and
disintegration rate (1).
E. Miscellaneous Factors
1. Personal Errors: Anomalous dissolution usually
involves some of following observations: floating chunks of
tablets, spinning, coning, mounding, gumming, swelling,
capping, off-center position, sticking, particles adhering to
apparatus or vessel walls, sacs, swollen/rubbery mass. A
well trained analyst can pinpoint many of such problems.
Along with good documentation, familiarity with the
dissolution behavior of the product is essential in quickly
identifying changes in stability or changes associated with a
modification of the formulation (1).
2. Cleaning: The analyst should take special care to
examine this aspect when validating the method. In many
laboratories, where different products are tested on the same
equipment, this is a critical issue that, if inadequately
monitored, may be a cause of inspection failures (1).
CONCLUSION
The dissolution test is sensitive to a nearly infinite
number of parameters, from characterizations of the drug to
formulation changes to, most importantly, manufacturing
parameters. The dissolution test's ability to show changes in
so many parameters is its power and its frustration. The
power of the test outweighs the frustration for one simple
reason: the dissolution test is the only test that has some
degree of relevance to the drug's therapeutic effect in vivo.
The push for more clinically relevant dissolution
specifications and methods is laudable, and in this effort, the
method-development stage is particularly critical. Many a
naïve manager has viewed the dissolution test as simple until
a problem occurs.
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