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Selection of Dissolution
Selection of Dissolution
Selection of Dissolution
Selection of Dissolution
Medium for QC Testing
of Drug Products
Gregory P. Martin and Vivian A. Gray
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 substance 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 adequate 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 understanding 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.
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SOLUBILITY CHARACTERIZATION
The solubility should be characterized over the physiological 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 identify 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.
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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 medium 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).
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As in the case of water-soluble drugs, once candidate pH values have been identified, empirical data
and visual observations are useful for selecting the
final medium conditions for the dissolution procedure. 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.
of
CMC (% wt/volume)
0.23% (14)
0.002% (15)
Cetyltrimethyl ammonium
bromide (CTAB, hexadecyltrimethylammonium bromide)
0.04% (14)
EVALUATION OF
ROBUSTNESS AND RUGGEDNESS
A phase-appropriate approach to evaluation of variability in dissolution testing is recommended. Early
in development, when there is relatively little experience with the dissolution method, results are generally accepted at face value. However, as development progresses, it is well recognized that issues with
robustness and ruggedness are not uncommon. These
may have profound effects, including additional testing and potential generation of out-of-specification
results. For these reasons, it is prudent to understand
the potential impact of variability as early in development as practical. This should include understanding 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-tobatch 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.
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EVALUATION OF
DISCRIMINATING POWER
Having selected a dissolution medium or a few candidates 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 discriminating 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 stability 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 valuable as justification of dissolution conditions in the
regulatory filing.
CONCLUSIONS
Selection of dissolution medium is a multi-step process. Early steps include identification of the requirements 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 discriminatory 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.
iv thome.com
4. FDA, Guidance for Industry Dissolution Testing of Immediate 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 Classification: The Correlation of In Vitro Drug Product
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, Dissolution Testing for Poorly Soluble Drugs: A Continuing 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
Sparingly Water-Soluble Drug Products, American Pharmaceutical Review, 16-21, Winter 2002.
10. Cynthia K. Brown, Hitesh P. Chokshi, Beverly Nickerson, Robert A. Reed, Brian R. Rohrs, and Pankaj A.
Shah, Acceptable Analytical Practices for Dissolution
Testing of Poorly Soluble Compounds, Pharmaceutical
Technology, 56-65, December 2004.
11. USP, USP 34-NF 29, May 2011.
12. R aimar L benberg , Johannes K rmer, Vinod P.
Shah,Gordon L. Amidon and Jennifer B. Dressman,
Dissolution Testing as a Prognostic Tool for Oral Drug
Absorption: Dissolution Behavior of Glibenclamide,
Pharmaceutical Research, Vol. 17, No. 4, 2000.
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