The document outlines requirements and considerations for dissolution testing of drug products in accordance with federal regulations, emphasizing the importance of setting dissolution acceptance criteria based on clinical and stability batch data. It details potential sources of variability in testing results, categorized into equipment, process, drug substance properties, and product properties, highlighting the need for consistent methodology and calibration. Additionally, it addresses the challenges of automation, the effects of drug properties on dissolution, and the significance of proper maintenance and training of analysts to ensure reliable test outcomes.

1. MEETING DISSOLUTION REQUIREMENTS,
PROBLEMS OF VARIABLE CONTROL IN
DISSOLUTION TESTING
PRESENTED BY-MUKESH KR BHAGAT
DEPARTMENT OF PHARMACEUTICS
2ND SEM M.PHARM
ABMRCP, Bangalore

2. MEETING DISSOLUTION REQUIREMENTS
According to the Code of Federal Regulations (CFR), a drug
product application should include the following
specifications necessary to ensure the
Identity,
 Strength,
 Quality,
Purity,
 Potency,
 Bioavailability of the drug product,
including, and acceptance criteria relating to, dissolution
rate in the case of solid dosage forms.

3. Dissolution acceptance criteria
 For the selection of the dissolution acceptance criteria, the
following points should be considered:
1.The dissolution profile data from the pivotal clinical batches and
primary (registration) stability batches should be used for the setting
of the dissolution acceptance criteria of your product (ie, specification-
sampling time point and specification value).
 A significant trend in the change in dissolution profile during
stability should be justified with dissolution profile comparisons and
in vivo data in those instances where the similarity testing fails

4. 2. Specifications should be established based on average in vitro
dissolution data for each lot under study, equivalent to USP Stage 2
testing (n = 12).
3. For immediate-release formulations, the last time point should be the
time point where at least 80% of drug has been released.
 If the maximum amount released is less than 80%, the last time point
should be the time when the plateau of the release profile has been
reached. Percent release of less than 80% should be justified with
data (eg, sink conditions information)

5. 4. For extended-release formulations, a minimum of three time points
is recommended to set the specifications. These time points should
cover the early, middle, and late stages of the release profile.
 The last time point should be the time point where at least 80% of
drug has been released. If the maximum amount released is less
than 80%, the last time point should be the time when the plateau of
the release profile has been reached.
5. The dissolution acceptance criterion should be set in a way to
ensure consistent performance from lot to lot, and this criterion should
not allow the release of any lots with dissolution profiles outside those
that were studied clinically.

6.  The term Q means the amount of drug dissolved within a given time
period established in the drug product specification table and is
expressed as a percentage of label content.
 For example, a value of Q = 80% at 30 minutes means that the mean
percent dissolved of 12 units individually tested is at least 80% at the
selected time point of 30 minutes.
 when implementing dissolution as a quality control tool for batch
release and stability analysis, the testing should follow the
recommendations listed in the USP method <711> for immediate-
release dosage forms and <724> for modified-release dosage forms.

7.  For example, for Stage 1, which considers the testing of 6 units,
each unit must meet the criterion of not less than 85% at 30
minutes for a drug product whose acceptance criterion was set
to Q = 80% at 30 minutes.
 Testing should continue through the three stages (S1, S2, S3)
unless the results conform at either Stage 1 or Stage 2 (Table
15-9)

8.  The USP-NF monographs may have multiple dissolution tests for
generic drug products that are approved by the FDA as therapeutic
equivalents.
 Although both the brand and approved generic drug products are
bioequivalent, their in vitro dissolution profiles may be different.
 Ideally, both methods should have very similar discriminating ability;
however, this can only be determined when an IVIVR or an IVIVC has
been established for the drug products rending the method not only
discriminating but also predictive of in vivo performance.

9. PROBLEMS OF VARIABLE CONTROL IN
DISSOLUTION TESTING
The source of deviation from accurate results in
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

10. 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
Some of the parameters associated
1. Dissolution Test Vessel
2. Paddle/ Basket Shaft
3. Vibrations
4. Use of Filters
5. Calibration of Dissolution Vessel

11. 1. Dissolution Test Vessel:
Dissolution testing is an attempt to create a perfectly controlled space, with a hydrodynamically
consistent environment. “Ideally the 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 molds. 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.”
Some have concluded that a major source of dissolution result variability appears to be the geometric
parameters of the dissolution vessel and stirring mechanism.
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.

12. The dissolution results of USP Prednisone Calibrator tablets were compared for the precision
vessel and vessel A. 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 .
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 .

13. 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 around the O-ring. The other has
three clips attached to the disk at the end of the shaft . The basket is attached by fitting between
the clips and the disk. There was no difference between the two basket shaft types for the three
development products.
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.
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" .

14. 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.
5. Calibration of Dissolution Apparatus:
The process by which a test apparatus is determined to meet the compendial (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).

15. 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.
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. De-airation 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 themonographs, 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.

16. 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 offcenter, 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 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.
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.
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. 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.
Additional examples in the literature suggest that the hydrodynamic conditions, drug release pattern, or
mechanical forces of anin vitro dissolution are crucial to the drug release rate.

17. 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. 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.
5. Controlled Release Dosage Forms
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 in vitro. Since most sustained or controlled release preparations are designed for
prolonged release and therapeutic effect, variabilities in in vivo 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.

18. 6. Automation:
While automation of dissolution sampling is very convenient and labor saving, 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
replacement.
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.

19. D. Drug Product Properties Related Factors
Dissolution profile may help in identifying trends and effects of formulation changes.
When the results are highly 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 .

20. 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 .
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.