A seminar on

DISSOLUTION TESTING

Presented by
Sukanya Patil, Zubiya Shah, and Mushahid Shaikh
(M Pharm sem II )

Under the guidance of

Dr. Jaya Agnihotri

Department of Pharmaceutics

H. K. College of Pharmacy
TABLE OF CONTENT:
 ALTERNATIVE METHODS OF DISSOLUTION TESTING

 MEETING DISSOLUTION REQUIREMENTS

 PROBLEMS OF VARIABLE CONTROL

 PERFORMANCE OF DRUG PRODUCTS IVIVC

 CATEGORIES OF IVIVC:
• LEVEL A CORRELATION
• LEVEL B CORRELATION
• LEVEL C CORRELATION
ALTERNATIVE METHODS OF
DISSOLUTION TESTING
(1)ROTATING BOTTLE METHOD:
The rotating bottle method was suggested in NF-XIII (National Formulary) but has become less popular since.
The rotating bottle method was used mainly for controlled-release beads. For this purpose the dissolution
medium may be easily changed, such as from artificial gastric juice to artificial intestinal juice. The equipment
consists of a rotating rack that holds the sample drug products in bottles. The bottles are capped tightly and
rotated in a 37°C temperature bath. At various times, the samples are removed from the bottle, decanted
through a 40-mesh screen, and the residues are assayed. An equal volume of fresh medium is added to the
remaining drug residues within the bottles and the dissolution test is continued. A dissolution test with pH 1.2
medium for 1 hour, pH 2.5 medium for the next 1 hour, followed by pH 4.5 medium for 1.5 hours, pH 7.0
medium for 1.5 hours, and pH 7.5 medium for 2 hours was recommended to simulate the condition of the
gastrointestinal tract. The main disadvantage is that this procedure is manual and tedious.
(2) INTRINSIC DISSOLUTION METHOD:

Most methods for dissolution deal with a finished drug product. Sometimes a new drug or substance may be
tested for dissolution without the effect of excipients or the fabrication effect of processing. The dissolution of
a drug powder by maintaining a constant surface area is called intrinsic dissolution. Intrinsic dissolution is
usually expressed as mg/cm2/min. In one method, the Basket method is adapted to test dissolution of powder
by placing the powder in a disk attached with a clipper to the bottom of the basket.

(3) PERISTALSIS METHOD:

The peristalsis method attempts to simulate the hydrodynamic conditions of the gastrointestinal tract in an in
vitro dissolution device. The apparatus consists of a rigid plastic cylindrical tubing fitted with a septum and
rubber stoppers at both ends. The dissolution chamber consists of a space between the septum and the lower
stopper. The apparatus is placed in a beaker containing the dissolution medium. The dissolution medium is
pumped with peristaltic action through the dosage form.
(4) DIFFUSION CELLS:

Static and flow-through diffusion cells are commercially available to

characterize in vitro drug release and drug permeation kinetics from
topically applied dosage form (eg, ointment, cream) or transdermal
drug product. The Franz diffusion cell is a static diffusion system that
is used for characterizing drug permeation through a skin model. The
source of skin may be human cadaver skin or animal skin (eg, hairless
mouse skin). Anatomically, each skin site (eg, abdomen, arm) has
different drug permeation qualities. The skin is mounted on the Franz
diffusion cell system. The drug product (eg, ointment) is placed on the
skin surface and the drug permeates across the skin into a receptor
fluid compartment that may be sampled at various times. The Franz
diffusion cell system is useful for comparing in vitro drug release
profiles and skin permeation characteristics to aid in selecting an
appropriate formulation that has optimum drug delivery.
(5) DISSOLUTION TESTING OF ENTERIC-COATED PRODUCTS:
USP-NF lists two methods (Method A and Method B), for testing enteric-coated products. The latest revision of the
USP-NF should be consulted for complete details of the methods.
Both methods require that the dissolution test be performed in the apparatus specified in the drug monograph (usually
Apparatus 2 or Apparatus 1). The product is first studied with 0.1 N HCl for 2 hours and then the medium is changed to
pH 6.8 buffer medium. The buffer stage generally runs for 45 minutes or for the time specified in the monograph. The
objective is that no significant dissolution occurs in the acid phase (less than 10% for any sample unit), and a specified
percentage of drug is released in the buffer phase. Dissolution acceptance criteria are defined in the individual drug
monographs for commercial products. Appropriate criteria will need to be established for novel drugs formulated as
enteric-coated drug products.

(6) DISSOLUTION APPROACHES FOR NOVEL/SPECIAL DOSAGE FORMS:

New or specialized dosage forms are being developed for improving patient compliance, to enhance therapeutic response
and for marketing exclusivity. Some of these dosage forms include osmotic capsules, orally disintegrating tablets,
medicated chewing gums, soft gelatin capsules containing drug dissolved in oil, nanomaterial, liposomal drug products,
implants, intrauterine devices, and drug-eluting stents. While conventional apparatus may be used to evaluate the
dissolution kinetics of nonconventional dosage forms, specialized or modified systems may be needed for others. For
example, medicated chewing gum and extended-release parenteral products may need a specialized dissolution apparatus
or a modified dissolution apparatus.
(7) USP PERFORMANCE VERIFICATION TEST AND MECHANICAL CALIBRATION
Dissolution is a complex system that mainly consists of three components:

(1) the analyst,

(2) the dissolution apparatus, and
(3) the analytical procedure/instrument.

In order for the dissolution test to be performed properly, and give meaningful results, these three components
must interact together optimally, or the results can be misleading. The USP general chapter for dissolution
includes performance verification test (PVT), to assure the suitability of Apparatus 1 and 2 when used for testing
drug products. PVT requires chemical calibration with calibrator tablets that may be obtained from USP-NF. The
calibration tablets, either prednisone tablets for dissolution tests requiring disintegrating tablets or salicylic acid
as a standard for non disintegrating tablets, are used to qualify USP dissolution Apparatus 1 and Apparatus 2.
PVT is also useful to compare performance of different dissolution apparatus used in different laboratories.
Mechanical calibration is a critical component of the qualification of the dissolution apparatus. The FDA has
introduced a mechanical calibration approach that considers mechanical specifications of the instrument design
and its manufacture (FDA Guidance for Industry, January 2010). Instead of using a calibrator tablet, a
pharmaceutical manufacturer can use an appropriately rigorous method of mechanical calibration for dissolution
Apparatus 1 and 2.
(8) DISCRIMINATING DISSOLUTION TEST
The value of in vitro dissolution testing is its ability to characterize drug products and assist in decision making
including
(1) ensuring quality control through a linkage to batches used in pivotal clinical studies;
(2) information on batch-to-batch consistency; and
(3) guide in formulation development.
Dissolution testing is the only product test that truly measures the effect of formulation and physical properties
of the active pharmaceutical ingredient (API) on the rate of drug solubilization. In addition, under certain
circumstances (eg, presence of an adequate IVIVC) in vitro dissolution testing can serve as a surrogate for
bioequivalence studies to assess the impact of some pre and post approval changes. The dissolution testing
procedure should be discriminating to ensure its value. A discriminating method is the one that is appropriately
sensitive to manufacturing changes. A discriminating method is able to differentiate drug products manufactured
under target conditions versus drug products that are intentionally manufactured with meaningful variations (ie,
±10%–20% change) to the specification ranges of the most relevant material attributes and manufacturing
variables (eg, drug substance particle size, polymorphism, compression force, tablet hardness, etc). The choice of
experimental design to evaluate the most relevant variables will depend on the design of the dosage form, the
manufacturing process, and intrinsic properties of the API.
MEETING DISSOLUTION REQUIREMENTS
According to the Code of Federal Regulations (CFR), a drug product application should include the
specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of
the drug product, including, and acceptance criteria relating to, dissolution rate in the case of solid
dosage forms. 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.

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).
MEETING DISSOLUTION REQUIREMENTS
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).

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.
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 per- centage 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. Note
that 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. 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).
PROBLEMS OF VARIABLE CONTROL
 As described above, various equipment and operating variables are associated with dissolution testing.
Understating the effects of operating conditions, the hydrodynamics and the geometric variables on the
velocity distribution in the dissolution system are critical to enhance the reliability of dissolution testing and
to avoid product recalls.
 Dissolution testing is a complex process involving various steps such as solid–liquid mass transfer, particle
erosion, possible particle disintegration, particle suspension, and particle–liquid interactions. However, this
process is further complicated by other factors such as shear stress distribution as a function of tablet location
within the apparatus, and the location of the tablet upon its release inside the apparatus.
 Depending on the particular dosage form involved, the variables may or may not exert a pronounced effect on
the rate of dissolution of the drug or drug product. Variations may occur with the same type of equipment and
procedure. The centering and alignment of the paddle is critical in the paddle method. Turbulence can create
increased agitation, resulting in a higher dissolution rate. Wobbling and tilting due to worn equipment should
be avoided. The basket method is less sensitive to the tilting effect. However, the basket method is more
sensitive to clogging due to gummy materials. Pieces of small particles can also clog up the basket screen and
create a local nonsink condition for dissolution. Furthermore, dissolved gas in the medium may form air
bubbles on the surface of the dosage form unit and can affect dissolution in both the basket and paddle
methods.
PERFORMANCE OF DRUG PRODUCTS
 IN VITRO- IN VIVO CORRELATION
 For controlled-release or extended-release formulation, since dissolution or release of the drug from the
formulation is the rate-limiting step in the appearance of the drug into the systemic circulation, it is possible
to establish a relationship between the release of the drug in vitro and its release in vivo or its absorption into
the systemic circulation. If such correlation exists, then one is able to predict the plasma concentration time
profile of a drug from its in vitro dissolution. Usually such a correlation is developed with two or more
formulations with different release characteristics. It is recommended that a correlation be established with
three or more formulations.

 However, if the dissolution of the drug is independent of the dissolution conditions (such as apparatus
agitation rate, pH, etc), then it is possible to establish such a correlation with only one formulation. The
establishment of a predictive IVIVC not only provides you with a better understanding of the release
properties of the drug product but also enables one to decrease the number of in vivo studies needed to
approve and maintain a drug product on the market resulting in an economic benefit as well as a decreased
regulatory burden. It also enables one to set clinically meaningful dissolution specifications based on the
predicted plasma concentration time profile.
A meaningful and predictive IVIVC is a correlation that is able to predict the Cmax and AUC within
20% (FDA guidance for industry, 1997b).

There are two ways in evaluating the predictability of the correlation:

(1) Internal predictability refers to the ability to predict the pharmacokinetic profile of the
formulations that were used to develop the correlation;

(2) External predictability refers to the ability to detect the profile of a lot or formulation that was not
used to develop the IVIVC. In the United States and in Europe, a bioequivalence study can be waived
based on the IVIVC if the predicted mean AUC and Cmax of the test and reference do not differ from
each other by more than 20% (US IVIVC guidance for industry; EMA, August 2012).
 CATEGORIES OF IVIVC
 LEVEL A CORRELATION:
 Level A correlation is the highest level of correlation and represents a point-to-point (1:1) relationship between
an in vitro dissolution and the in vivo input rate of the drug from the dosage form. Level A correlation
compares the percent (%) drug released versus percent (%) drug absorbed. Generally, the percentage of drug
absorbed may be calculated by the Wagner-Nelson or Loo–Riegelman procedures or by direct mathematical
deconvolution, a process of mathematical resolution of blood level into an input (absorption) and an output
(disposition) component.

 The major advantage of a Level A correlation is that a point-to-point correlation is developed. All in vitro
dissolution data and all in vivo plasma drug concentration–time profile data are used. Once a Level A
correlation is established, an in vitro dissolution profile can serve as a surrogate for in vivo performance. A
change in manufacturing site, method of manufacture, raw material supplies, minor formulation modification,
and even product strength using the same formulation can be justified without the need for additional human
studies. Level A correlation enables the in vitro dissolution test to become meaningful and clinically relevant
quality control test that can predict in vivo drug product performance.
 LEVEL B CORRELATION:
Level B correlation utilizes the principle of statistical moment in which the mean in vitro dissolution time is
compared to either the mean residence time (MRT)2 or the mean in vivo dissolution time (MDT). Level B
correlation uses all of the in vitro and in vivo data, but is not a point-to-point correlation. Different profiles can
give the same parameter values. The Level B correlation alone cannot justify formulation modification,
manufacturing site change, excipient source change, batch-to-batch quality, etc.

 LEVEL C CORRELATION:
A Level C correlation is not a point-to-point correlation. A Level C correlation establishes a single-point
relationship between a dissolution parameter such as percent dissolved at a given time and a pharmacokinetic
parameter of interest such as AUC and Cmax. Level C correlation is useful for formulation selection and
development but has limited application. Multiple Level C correlation relates one or several pharmacokinetic
parameters of interest to the amount of drug dissolved at several time points of the dissolution profile. In general,
if one is able to develop a multiple Level C correlation, then it may be feasible to develop a Level A correlation.
Several examples of Level C correlation are given as followed.
 Dissolution rate versus absorption rate

If dissolution of the drug is rate limiting, a faster dissolution rate may

result in a faster rate of appearance of the drug in the plasma. It may be
possible to establish a correlation between rate of dissolution and rate of
absorption of the drug. The absorption rate is usually more difficult to
determine than peak absorption time. Therefore, the absorption time may
be used in correlating dissolution data to absorption data. In the analysis
of in vitro–in vivo drug correlation, rapid drug dissolution may be
distinguished from the slower drug absorption by observation of the
absorption time for the preparation. The absorption time refers to the
time for a constant amount of drug to be absorbed. In one study
involving three sustained-release aspirin products (Levy et al, 1965), the
dissolution times for the preparations were linearly correlated to the
absorption times (Fig. 15-14). The results from this study demonstrated
that aspirin was rapidly absorbed and was very much dependent on the
dissolution rate for absorption.
 Percent of drug dissolved versus percent of drug absorbed

If a drug is absorbed completely after dissolution, a linear

correlation may be obtained by comparing the percentage of
drug absorbed to the percentage of drug dissolved. In choosing
the dissolution method, one must consider the appropriate
dissolution medium and use a slow dissolution stirring rate so
that in vivo dissolution is approximated. Aspirin is absorbed
rapidly, and a slight change in formulation may be reflected in
a change in the amount and rate of drug absorption during the
period of observation (see Figs. 15-14 and 15-15). If the drug
is absorbed slowly, which occurs when absorption is the rate-
limiting step, a difference in dissolution rate of the product
may not be observed. In this case, the drug would be absorbed
very slowly independent of the dissolution rate.
 Maximum plasma concentrations versus percent
of drug dissolved in vitro
When different drug formulations are studied for dissolution, a poorly
formulated drug may not be completely dissolved and released, resulting in
lower plasma drug concentrations. The percentage of drug released at any
time interval will be greater for the more bioavailable drug product. When
such drug products are studied in vivo, the peak drug serum concentration
will be higher for the drug product that shows the highest percent of drug
dissolved. An example of in vitro–in vivo correlation for 100-mg phenytoin
sodium capsules is shown in Fig. 15-16. Several products were tested (Shah
et al, 1983). A linear correlation was observed between the maximum drug
concentration in the body and the percent of drug dissolved in vitro. The
dissolution study on the phenytoin sodium products (Shah et al, 1983)
showed that the fastest dissolution rate was product C, for which about
100% of the labeled contents dissolved in the test (Fig. 15-17).
Interestingly, these products also show the shortest time to reach peak
concentration (tmax). The tmax is dependent on the absorption rate
constant. In this case, the fastest absorption would also result in the shortest
tmax.
 Serum drug concentration versus percent of drug dissolved

In a study on aspirin absorption, the serum

concentration of aspirin was correlated to the
percent of drug dissolved using an in vitro
dissolution method (Wood, 1966). The
dissolution medium was simulated gastric juice.
Because aspirin is rapidly absorbed from the
stomach, the dissolution of the drug is the rate-
limiting step, and various formulations with
different dissolution rates will cause differences
in the serum concentration of aspirin by minutes
(Fig. 15-18).
THANK YOU!!!