Dissolution Concepts and Applications.

Gregory P. Martin and Vivian A. Gray ]

Selection of Dissolution
Medium for QC Testing
of Drug Products
Gregory P. Martin and Vivian A. Gray

Dissolution Concepts and Applications provides a
forum for sharing information about topics associ-
ated with in vitro dissolution testing. Our objective
for this feature: Useful and practical information
applicable to daily work situations.
Reader comments, questions, and suggestions
are needed to help us fulfill the column objective.
Please send your comments and suggestions to col-
umn coordinators Vivian Gray at vagray@rcn.com
or Greg Martin at greg.martin@complectors.com,
or to managing editor Susan Haigney at shaigney@
advanstar.com.
KEY POINTS
The following key points are discussed:
Selection of the dissolution medium to be used
for quality control dissolution testing is the most
critical part of dissolution method development.
The analytical target profile (ATP) and drug sub-
stance solubility are key factors in dissolution
medium selection.
The ATP should indicate the type of dosage form
for which the test is being developed.
Drug substance solubility should be characterized
over the physiological range of pH values.
Soluble drugs exhibit good solubility across the
physiological pH range (e.g., sink conditions at
pH 1.2, 4.5, and 6.8 or BCS Class I/III).
Drugs with pH-dependent solubility exhibit ade-
quate solubility (sink conditions) over part, but
not all, of the physiological pH range depending
on the pKa. The dissolution medium selected
for these drugs usually is at the pH that provides
sink conditions.
Poorly soluble drugs often use surfactants to
increase solubility. Surfactants may reduce surface
tension (lower concentrations) or solubilize drugs
via micelle formation at concentrations above the
critical micelle concentration.
Robustness and ruggedness of the dissolution
method should be evaluated. This includes under-
standing sensitivity of solubility or dissolution
results to changes in pH, solution stability of the
drug in the medium, and other considerations.
Discriminating power of the dissolution test
should be evaluated. This is done by intentionally
introducing changes to the formulation, process,
or other parameters and determining the impact
on dissolution results.
INTRODUCTION
This column previously discussed an overall approach
to the development of dissolution methods. This
discussion addresses the most critical part of that
process: selection of the medium to be used for quality
control (QC) dissolution testing.

[
ABOUT THE AUTHORS
For more Author Gregory P. Martin is president of Complectors Consulting (www.complectors.com), which provides
information, consulting and training in the area of pharmaceutical analytical chemistry. He may be contacted at greg.
go to martin@complectors.com. Vivian A. Gray has spent the last 35 years involved in all aspects of dissolu-
gxpandjvt.com/bios tion testing and evaluating new dissolution technology. In 2002, she began a consulting business, V.A.
Gray Consulting, Inc., in dissolution testing and related areas. She may be contacted at vagary@rcn.com.

gxpandjv t.com Journal of Validation T echnology [Summer 2011] 7

Dissolution Concepts and Applications.
While dissolution testing is utilized for a number of
reasons including formulation selection and establish-
ment of an in-vitro in-vivo correlation (IVIVC), by far
the most frequent application is QC testing for release
or stability purposes. And while choice of appara-
tus or analytical technique for samples may be fairly
straightforward, the choice of dissolution medium can
be very challenging. The dissolution medium must
meet regulatory requirements in a global environment,
balance discriminating ability with robustness, and
lead to development of an appropriate specification.
Prior to embarking on the path to identify an opti-
mal dissolution medium, it is best to have addressed
two major items: analytical target profile (ATP) (1) and
characterization of drug substance solubility. These are
useful for selection of medium. A decision tree will be
presented that may be useful for the selection process.
Subsequent to the initial selection of candidate media,
it is necessary to generate some empirical data with
real samples to evaluate the suitability of the medium
choices. When feasible, it can be a valuable exercise to
conduct additional experiments to evaluate the dis-
criminating ability of the dissolution method, usually
involving some manufacturing variability or stressed
samples. The establishment of acceptance criteria logi-
cally follows this sequence of events.
ANALYTICAL TARGET PROFILE
The ATP should indicate the type of dosage form for
which the test is being developed. This may have
significant impact on the selection of medium. For
instance, if the product is intended to have delayed
release (2), a two-media test starting with a low pH
medium (demonstrating lack of release under simu-
lated gastric conditions) followed with a higher pH
medium (simulating intestinal condition) is appropri-
ate. If the product is intended to have extended release
properties, a medium with a higher pH (simulating
intestinal conditions) is appropriate. The ATP should
also address the expectations regarding discriminating
power, which can be useful for evaluating data from
experiments designed to probe that aspect.
SOLUBILITY CHARACTERIZATION
The solubility should be characterized over the physi-
ological range of pH values, generally pH 1.2 to 6.8
for immediate release products, and pH 1.2 to 7.5 for
extended release products (3). It is also useful to iden-
tify the pKa value(s) for the drug substance, if there are
any, because ionization can have a profound impact
on aqueous solubility and should be well understood.
8 Journal of Validation T echnology [Summer 2011]
When the drug is poorly water soluble, solubility in
surfactant solutions may be investigated (4).
There are a few ways to define poorly soluble. Tra-
ditionally with dissolution, the term sink has been
used, with a definition (in recent years) that volume
of medium is at least three times that required to form
a saturated solution (3). Alternatively, the Biopharma-
ceutics Classification System (BCS) stipulates that the
dose should be soluble in 250 mL (5). The definitions
are similar, and both describe a dissolution system that
is sufficiently dilute so that the dissolution process is
not impeded by saturation of the compound of inter-
est. Sink conditions are generally recommended but
not always required, and non-sink conditions may
lead to greater discrimination.
WATER SOLUBLE DRUGS
Soluble drugs exhibit good solubility across the physi-
ological pH range (e.g., sink conditions at pH 1.2, 4.5,
and 6.8 or BCS Class I/III). The choice of dissolution
medium pH is flexible for these drugs. Also, it is less
likely that the dissolution test will be discriminating
for these drugs.
The pH of the medium should be chosen from
the physiological pH range. Ionic strength of buffers
should be the same as in the United States Pharmaco-
peia (USP) (6). Note that for some drugs, incompat-
ibility of the drug with certain buffers or salts may
influence the choice of buffer. Water is a potential
choice, although it is not recommended because test
conditions, such as pH and surface tension, can vary
depending on the source of water and may change
during the dissolution test itself due to the influence
of the active and inactive ingredients (4). Dissolution
medium with pH similar to that of a pKa (+/- 1 pH
unit) should be avoided because variation in the degree
of ionization could have an impact on the ruggedness
of the dissolution procedure. Selection of a pH where
the solubility is at a minimum may assist in accom-
plishing a discriminating method. Solution stability
can be an issue, even if it appears the drug is soluble.
Solution stability in the dissolution medium should
be understood before investing significant effort in
dissolution testing.
When water solubility is good, typically media with
pH of 1.2, 4.5, and 6.8 are starting points for medium
selection. USP buffers (e.g., hydrochloric, acetate, and
phosphate buffers, respectively) are recommended.
Empirical data using manufactured dosage forms
and potential media may be useful for selecting the
actual dissolution conditions. Results, such as the time
iv thome.com

to reach full dissolution or variability between vessels,
may influence the selection of the medium chosen.
During the method development phase, it is often
useful to make visual observations during the disso-
lution procedure. It is especially important to make
notes when observations among vessels are different
when using the same medium.
It is useful to check the pH both before and after
the dissolution test to assess whether the medium had
sufficient buffer capacity to maintain consistent pH. If
the pH changes during the dissolution test (which may
be due to the properties of the drug substance or the
excipients), consider increasing the buffer concentra-
tion, using a different buffer, or using a different pH.
In some cases, the concentration of the USP buffers
(nominally 0.05M) may result in precipitation during
the analysis of the samples, particularly when using
HPLC with a mobile phase with a high percentage of
organic. It is acceptable to reduce the buffer concentra-
tion, as long as a consistent pH is maintained during
the dissolution test. Changes in the concentration of
the buffer may result in changes in the dissolution rate.
When dissolution is rapid (>80% dissolved in 15
minutes) at the three pH values mentioned, it may
be possible to use disintegration instead of dissolu-
tion. A decision tree in International Conference on
Harmonisation (ICH) Q6 permits this if a relationship
can be established between dissolution and disinte-
gration results.
If the product is being developed for global market-
ing, it may be prudent to avoid acidic conditions (e.g.,
pH 1.2 or simulated gastric fluid) due to a preference
of the Japanese regulators to avoid this condition (7).
DRUGS WITH
pH-DEPENDENT SOLUBILITY
Drugs with pH-dependent solubility exhibit adequate
solubility (sink conditions) over part, but not all, of
the physiological pH range. The dissolution medi-
um selected for these drugs usually is at the pH that
provides sink conditions. Knowledge of the pKa, the
impact of pKa on the solubility, and the ruggedness
of the dissolution procedure must be considered.
In this situation, start with conditions where sink
conditions have been demonstrated (usually one or
two of the initial target values of pH 1.2, 4.5, or 6.8).
It often makes sense to investigate intermediate pH
values. Where solubility increases with increasing pH,
buffers with pH up to 8.0 may be selected, if justified
(i.e., the ATP requirements are not met at pH below
pH 6.8, but are met at higher pH).
gxpandjv t.com
Gregory P. Martin and Vivian A. Gray.
As in the case of water-soluble drugs, once candi-
date pH values have been identified, empirical data
and visual observations are useful for selecting the
final medium conditions for the dissolution proce-
dure. The probability of identifying a discriminating
dissolution procedure is greater than in the case of
a water-soluble drug. Experiments for evaluating
ability to discriminate are described later in this
discussion.
POORLY WATER-SOLUBLE DRUGS
The incidence of new drug candidates that are poor-
ly water-soluble has been increasing. A variety of
approaches to solubilize these drugs including nano-
formulations, hot-melt extrusion, and oil-filled soft
gelatin capsules (8) are being used. These formulations
create a challenge for choosing a dissolution medium.
Addition of surfactants is often used to increase
solubility. Sodium dodecyl sulfate (SDS) and polysor-
bate 80 (Tween 80) have been used most frequently.
A number of other surfactants have also been used (9,
10). The US Food and Drug Administration discourage
the use of hydroalcoholic media (4). A recent search
of USP monographs indicated over 60 monographs
that use SDS as a dissolution medium, and at least
20 monographs that use polysorbate 80 (11). Endog-
enous surfactants, including sodium taurocholate
and sodium deoxycholate, have been used for some
biorelevant dissolution procedures (12). These are
generally not appropriate for a quality control applica-
tion due to cost and difficulty in preparation. Glob-
al considerations can influence choice of medium.
Japanese regulators have been known to favor use of
polysorbate 80 for poorly water-soluble compounds,
as described in their guideline for bioequivalence of
generic products (13).
When using surfactants, several parameters must be
investigated. Select the lowest concentration that meets
the requirements of the ATP (typically >80% within a
specified time frame, and acceptable reproducibility).
As with aqueous solutions, control of pH can be criti-
cal. There may be effects of counter-ions or pH on the
solubility or solution stability of the surfactant solutions.
There are two mechanisms by which surfactants can
enhance dissolution results: reduction of surface tension
(at lower concentrations) or solubilization via micelle
formation at concentrations above the critical micelle
concentration (CMC). For dissolution of poorly water-
soluble compounds, typically concentrations above the
CMC are employed. The Table lists the CMC concen-
tration for typical surfactants used in dissolution test-
Journal of Validation T echnology [Summer 2011] 9
Dissolution Concepts and Applications.
Table: Critical micelle concentrations
of common surfactants.
Name CMC (% wt/volume)
Sodium dodecyl sulfate (SDS, 0.23% (14)
sodium lauryl sulfate, SLS)
Polysorbate 80 (Polyoxyethyl- 0.002% (15)
ene 80) sorbitan monooleate,
Tween 80)
Cetyltrimethyl ammonium 0.04% (14)
bromide (CTAB, hexadecyltri-
methylammonium bromide)
ing. However, if the drug substance or drug product has
poor wetability, then using surfactants at relatively low
concentrations (below CMC) to reduce surface tension
may be successful in improving dissolution results. Nor-
mally, the lowest effective concentration is used for the
dissolution procedure, based on empirical results using
manufactured dosage forms.
Experience has demonstrated that it is important to
control the grade and consistency of surfactants used
for dissolution testing. For example, SDS is available in
both a technical grade and a high purity grade; also, the
source of polysorbate 80 can affect its suitability when
using a chromatographic determination.
EVALUATION OF
ROBUSTNESS AND RUGGEDNESS
A phase-appropriate approach to evaluation of vari-
ability in dissolution testing is recommended. Early
in development, when there is relatively little expe-
rience with the dissolution method, results are gen-
erally accepted at face value. However, as develop-
ment progresses, it is well recognized that issues with
robustness and ruggedness are not uncommon. These
may have profound effects, including additional test-
ing and potential generation of out-of-specification
results. For these reasons, it is prudent to understand
the potential impact of variability as early in develop-
ment as practical. This should include understand-
ing sensitivity of solubility or dissolution results
to changes in pH around the value chosen for the
medium. Solution stability of the drug in the medium
and stability of the dissolution medium itself must
be understood. Apparatus-to-apparatus and batch-to-
batch effects should also be evaluated. The impact of
storage conditions on the dissolution characteristics of
the dosage form should be studied. It may be feasible
to reduce variability in dissolution results by choosing
an alternative dissolution medium.
10 Journal of Validation T echnology [Summer 2011]
EVALUATION OF
DISCRIMINATING POWER
Having selected a dissolution medium or a few can-
didates for dissolution media, it is often useful to
probe the discriminating power of the dissolution test.
Regulators are often interested in knowing whether
the dissolution medium is capable of discriminat-
ing between good and poor batches. In an ideal
world, batches with acceptable and unacceptable
characteristics in patients would be available, and
the evaluation straightforward. This is rarely the case.
Nonetheless, to probe the discriminating power of the
dissolution procedure, in addition to evaluating the
robustness and ruggedness of the procedure, it may
be useful to intentionally introduce changes to the
formulation. This may be accomplished by modifying
the manufacturing process or by stressing samples
in a manner that is more intense than typical stabil-
ity testing. For example, manufacturing parameters
such as compression force or formulation lubricant
levels might be varied and the impact on dissolution
results determined. This type of data may be valu-
able as justification of dissolution conditions in the
regulatory filing.
CONCLUSIONS
Selection of dissolution medium is a multi-step pro-
cess. Early steps include identification of the require-
ments in the ATP and characterizing the solubility and
pKa(s) of the drug substance. With this information in
hand, selection of candidate media that exhibit sink
conditions can be undertaken. Final selection of the
actual medium for the test is based on empirical data
using dissolution results from manufactured dosage
forms in the various candidate media. This process is
enhanced when visual observations are made. When
appropriate for the phase of development, additional
data demonstrating robustness, ruggedness, and dis-
criminatory power can be used to refine the selection
of the medium.
REFERENCES
1. Nethercote, P., Borman, P., Bennett, T., Martin, G.P.,
McGregor, P., QbD for Better Method Validation and
Transfer, Pharmaceutical Manufacturing, 37-49, April
2010.
2. USP, General Chapter 711 Dissolution, USP 34-NF 29,
May 2011.
3. USP, General Chapter 1092 The Dissolution Procedure
Development and Validation, USP 34-NF 29, May 2011.
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4. FDA, Guidance for Industry Dissolution Testing of Immedi-
ate Release Solid Oral Dosage Forms, FDA, CDER, August
1997.
5. Amidon G. L., Lennerns H., Shah V. P., Crison J. R.,
A Theoretical Basis For A Biopharmaceutic Drug Clas-
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Dissolution and In Vivo Bioavailability, Pharm Res.;
12(3):413420, 1995.
6. USP, Buffer Solutions, USP 34-NF 29, May 2011.
7. Vivian Gray, Meeting Report: University of Wisconsin/
AAPS/FDA Workshop-Applied Biopharmaceutics and
Quality by Design for Dissolution/Release Specification
Stting: Product Quality for Patient Benefit, Dissolution
Technologies, November 2009.
8. K. Gowthamarajan1 and Sachin Kumar Singh, Dis-
solution Testing for Poorly Soluble Drugs: A Continu-
ing Perspective, Dissolution Technologies, 24-32, August
2010.
9. Carol Noory, Nhan Tran, Larry Ouderkirk, and Vinod
Shah, Steps for Development of a Dissolution Test for
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maceutical Review, 16-21, Winter 2002.
10. Cynthia K. Brown, Hitesh P. Chokshi, Beverly Nick-
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Technology, 56-65, December 2004.
11. USP, USP 34-NF 29, May 2011.
12. R aimar L benberg , Johannes K rmer, Vinod P.
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Dissolution Testing as a Prognostic Tool for Oral Drug
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Gregory P. Martin and Vivian A. Gray.
13. NIHS, Guideline for Bioequivalence Studies of Generic
Products, National Institute of Health Sciences (NIHS),
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14. P. Mukerjee and K. J. Mysels, Critical Micelle Concen-
tration of Aqueous Surfactant Systems, NSRDS-NBS
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JF, Manning MC, Effects of Tween 20 and Tween 80 on
the stability of Albutropin during agitation, J Pharm Sci
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ARTICLE ACRONYM LISTING
ATP Analytical Target Profile
BCS Biopharmaceutics Classification System
CMC Critical Micelle Concentration
FDA US Food and Drug Administration
ICH International Conference on Harmonisation
IVIVC In Vitro In Vivo Correlation
pKa (Acid) dissociation constant or ionization
constant
QC Quality Control
SDS Sodium Dodecyl Sulfate
USP United States Pharmacopeia
Journal of Validation T echnology [Summer 2011] 11