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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 Drugs with pH-dependent solubility exhibit ade-
forum for sharing information about topics associ- quate solubility (sink conditions) over part, but
ated with in vitro dissolution testing. Our objective not all, of the physiological pH range depending
for this feature: Useful and practical information on the pKa. The dissolution medium selected
applicable to daily work situations. for these drugs usually is at the pH that provides
Reader comments, questions, and suggestions sink conditions.
are needed to help us fulfill the column objective. Poorly soluble drugs often use surfactants to
Please send your comments and suggestions to col- increase solubility. Surfactants may reduce surface
umn coordinators Vivian Gray at vagray@rcn.com tension (lower concentrations) or solubilize drugs
or Greg Martin at greg.martin@complectors.com, via micelle formation at concentrations above the
or to managing editor Susan Haigney at shaigney@ critical micelle concentration.
advanstar.com. Robustness and ruggedness of the dissolution
method should be evaluated. This includes under-
KEY POINTS standing sensitivity of solubility or dissolution
The following key points are discussed: results to changes in pH, solution stability of the
Selection of the dissolution medium to be used drug in the medium, and other considerations.
for quality control dissolution testing is the most Discriminating power of the dissolution test
critical part of dissolution method development. should be evaluated. This is done by intentionally
The analytical target profile (ATP) and drug sub- introducing changes to the formulation, process,
stance solubility are key factors in dissolution or other parameters and determining the impact
medium selection. on dissolution results.
The ATP should indicate the type of dosage form
for which the test is being developed. INTRODUCTION
Drug substance solubility should be characterized This column previously discussed an overall approach
over the physiological range of pH values. to the development of dissolution methods. This
Soluble drugs exhibit good solubility across the discussion addresses the most critical part of that
physiological pH range (e.g., sink conditions at process: selection of the medium to be used for quality
pH 1.2, 4.5, and 6.8 or BCS Class I/III). 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 When the drug is poorly water soluble, solubility in
reasons including formulation selection and establish- surfactant solutions may be investigated (4).
ment of an in-vitro in-vivo correlation (IVIVC), by far There are a few ways to define poorly soluble. Tra-
the most frequent application is QC testing for release ditionally with dissolution, the term sink has been
or stability purposes. And while choice of appara- used, with a definition (in recent years) that volume
tus or analytical technique for samples may be fairly of medium is at least three times that required to form
straightforward, the choice of dissolution medium can a saturated solution (3). Alternatively, the Biopharma-
be very challenging. The dissolution medium must ceutics Classification System (BCS) stipulates that the
meet regulatory requirements in a global environment, dose should be soluble in 250 mL (5). The definitions
balance discriminating ability with robustness, and are similar, and both describe a dissolution system that
lead to development of an appropriate specification. is sufficiently dilute so that the dissolution process is
Prior to embarking on the path to identify an opti- not impeded by saturation of the compound of inter-
mal dissolution medium, it is best to have addressed est. Sink conditions are generally recommended but
two major items: analytical target profile (ATP) (1) and not always required, and non-sink conditions may
characterization of drug substance solubility. These are lead to greater discrimination.
useful for selection of medium. A decision tree will be
presented that may be useful for the selection process. WATER SOLUBLE DRUGS
Subsequent to the initial selection of candidate media, Soluble drugs exhibit good solubility across the physi-
it is necessary to generate some empirical data with ological pH range (e.g., sink conditions at pH 1.2, 4.5,
real samples to evaluate the suitability of the medium and 6.8 or BCS Class I/III). The choice of dissolution
choices. When feasible, it can be a valuable exercise to medium pH is flexible for these drugs. Also, it is less
conduct additional experiments to evaluate the dis- likely that the dissolution test will be discriminating
criminating ability of the dissolution method, usually for these drugs.
involving some manufacturing variability or stressed The pH of the medium should be chosen from
samples. The establishment of acceptance criteria logi- the physiological pH range. Ionic strength of buffers
cally follows this sequence of events. should be the same as in the United States Pharmaco-
peia (USP) (6). Note that for some drugs, incompat-
ANALYTICAL TARGET PROFILE ibility of the drug with certain buffers or salts may
The ATP should indicate the type of dosage form for influence the choice of buffer. Water is a potential
which the test is being developed. This may have choice, although it is not recommended because test
significant impact on the selection of medium. For conditions, such as pH and surface tension, can vary
instance, if the product is intended to have delayed depending on the source of water and may change
release (2), a two-media test starting with a low pH during the dissolution test itself due to the influence
medium (demonstrating lack of release under simu- of the active and inactive ingredients (4). Dissolution
lated gastric conditions) followed with a higher pH medium with pH similar to that of a pKa (+/- 1 pH
medium (simulating intestinal condition) is appropri- unit) should be avoided because variation in the degree
ate. If the product is intended to have extended release of ionization could have an impact on the ruggedness
properties, a medium with a higher pH (simulating of the dissolution procedure. Selection of a pH where
intestinal conditions) is appropriate. The ATP should the solubility is at a minimum may assist in accom-
also address the expectations regarding discriminating plishing a discriminating method. Solution stability
power, which can be useful for evaluating data from can be an issue, even if it appears the drug is soluble.
experiments designed to probe that aspect. Solution stability in the dissolution medium should
be understood before investing significant effort in
SOLUBILITY CHARACTERIZATION dissolution testing.
The solubility should be characterized over the physi- When water solubility is good, typically media with
ological range of pH values, generally pH 1.2 to 6.8 pH of 1.2, 4.5, and 6.8 are starting points for medium
for immediate release products, and pH 1.2 to 7.5 for selection. USP buffers (e.g., hydrochloric, acetate, and
extended release products (3). It is also useful to iden- phosphate buffers, respectively) are recommended.
tify the pKa value(s) for the drug substance, if there are Empirical data using manufactured dosage forms
any, because ionization can have a profound impact and potential media may be useful for selecting the
on aqueous solubility and should be well understood. actual dissolution conditions. Results, such as the time

8 Journal of Validation T echnology [Summer 2011] iv thome.com


Gregory P. Martin and Vivian A. Gray.

to reach full dissolution or variability between vessels, As in the case of water-soluble drugs, once candi-
may influence the selection of the medium chosen. date pH values have been identified, empirical data
During the method development phase, it is often and visual observations are useful for selecting the
useful to make visual observations during the disso- final medium conditions for the dissolution proce-
lution procedure. It is especially important to make dure. The probability of identifying a discriminating
notes when observations among vessels are different dissolution procedure is greater than in the case of
when using the same medium. a water-soluble drug. Experiments for evaluating
It is useful to check the pH both before and after ability to discriminate are described later in this
the dissolution test to assess whether the medium had discussion.
sufficient buffer capacity to maintain consistent pH. If
the pH changes during the dissolution test (which may POORLY WATER-SOLUBLE DRUGS
be due to the properties of the drug substance or the The incidence of new drug candidates that are poor-
excipients), consider increasing the buffer concentra- ly water-soluble has been increasing. A variety of
tion, using a different buffer, or using a different pH. approaches to solubilize these drugs including nano-
In some cases, the concentration of the USP buffers formulations, hot-melt extrusion, and oil-filled soft
(nominally 0.05M) may result in precipitation during gelatin capsules (8) are being used. These formulations
the analysis of the samples, particularly when using create a challenge for choosing a dissolution medium.
HPLC with a mobile phase with a high percentage of Addition of surfactants is often used to increase
organic. It is acceptable to reduce the buffer concentra- solubility. Sodium dodecyl sulfate (SDS) and polysor-
tion, as long as a consistent pH is maintained during bate 80 (Tween 80) have been used most frequently.
the dissolution test. Changes in the concentration of A number of other surfactants have also been used (9,
the buffer may result in changes in the dissolution rate. 10). The US Food and Drug Administration discourage
When dissolution is rapid (>80% dissolved in 15 the use of hydroalcoholic media (4). A recent search
minutes) at the three pH values mentioned, it may of USP monographs indicated over 60 monographs
be possible to use disintegration instead of dissolu- that use SDS as a dissolution medium, and at least
tion. A decision tree in International Conference on 20 monographs that use polysorbate 80 (11). Endog-
Harmonisation (ICH) Q6 permits this if a relationship enous surfactants, including sodium taurocholate
can be established between dissolution and disinte- and sodium deoxycholate, have been used for some
gration results. biorelevant dissolution procedures (12). These are
If the product is being developed for global market- generally not appropriate for a quality control applica-
ing, it may be prudent to avoid acidic conditions (e.g., tion due to cost and difficulty in preparation. Glob-
pH 1.2 or simulated gastric fluid) due to a preference al considerations can influence choice of medium.
of the Japanese regulators to avoid this condition (7). Japanese regulators have been known to favor use of
polysorbate 80 for poorly water-soluble compounds,
DRUGS WITH as described in their guideline for bioequivalence of
pH-DEPENDENT SOLUBILITY generic products (13).
Drugs with pH-dependent solubility exhibit adequate When using surfactants, several parameters must be
solubility (sink conditions) over part, but not all, of investigated. Select the lowest concentration that meets
the physiological pH range. The dissolution medi- the requirements of the ATP (typically >80% within a
um selected for these drugs usually is at the pH that specified time frame, and acceptable reproducibility).
provides sink conditions. Knowledge of the pKa, the As with aqueous solutions, control of pH can be criti-
impact of pKa on the solubility, and the ruggedness cal. There may be effects of counter-ions or pH on the
of the dissolution procedure must be considered. solubility or solution stability of the surfactant solutions.
In this situation, start with conditions where sink There are two mechanisms by which surfactants can
conditions have been demonstrated (usually one or enhance dissolution results: reduction of surface tension
two of the initial target values of pH 1.2, 4.5, or 6.8). (at lower concentrations) or solubilization via micelle
It often makes sense to investigate intermediate pH formation at concentrations above the critical micelle
values. Where solubility increases with increasing pH, concentration (CMC). For dissolution of poorly water-
buffers with pH up to 8.0 may be selected, if justified soluble compounds, typically concentrations above the
(i.e., the ATP requirements are not met at pH below CMC are employed. The Table lists the CMC concen-
pH 6.8, but are met at higher pH). tration for typical surfactants used in dissolution test-

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Dissolution Concepts and Applications.

Table: Critical micelle concentrations EVALUATION OF


of common surfactants. DISCRIMINATING POWER
Name CMC (% wt/volume)
Having selected a dissolution medium or a few can-
didates for dissolution media, it is often useful to
Sodium dodecyl sulfate (SDS, 0.23% (14) probe the discriminating power of the dissolution test.
sodium lauryl sulfate, SLS)
Regulators are often interested in knowing whether
Polysorbate 80 (Polyoxyethyl- 0.002% (15) the dissolution medium is capable of discriminat-
ene 80) sorbitan monooleate, ing between good and poor batches. In an ideal
Tween 80) world, batches with acceptable and unacceptable
Cetyltrimethyl ammonium 0.04% (14) characteristics in patients would be available, and
bromide (CTAB, hexadecyltri- the evaluation straightforward. This is rarely the case.
methylammonium bromide) Nonetheless, to probe the discriminating power of the
dissolution procedure, in addition to evaluating the
ing. However, if the drug substance or drug product has robustness and ruggedness of the procedure, it may
poor wetability, then using surfactants at relatively low be useful to intentionally introduce changes to the
concentrations (below CMC) to reduce surface tension formulation. This may be accomplished by modifying
may be successful in improving dissolution results. Nor- the manufacturing process or by stressing samples
mally, the lowest effective concentration is used for the in a manner that is more intense than typical stabil-
dissolution procedure, based on empirical results using ity testing. For example, manufacturing parameters
manufactured dosage forms. such as compression force or formulation lubricant
Experience has demonstrated that it is important to levels might be varied and the impact on dissolution
control the grade and consistency of surfactants used results determined. This type of data may be valu-
for dissolution testing. For example, SDS is available in able as justification of dissolution conditions in the
both a technical grade and a high purity grade; also, the regulatory filing.
source of polysorbate 80 can affect its suitability when
using a chromatographic determination. CONCLUSIONS
Selection of dissolution medium is a multi-step pro-
EVALUATION OF cess. Early steps include identification of the require-
ROBUSTNESS AND RUGGEDNESS ments in the ATP and characterizing the solubility and
A phase-appropriate approach to evaluation of vari- pKa(s) of the drug substance. With this information in
ability in dissolution testing is recommended. Early hand, selection of candidate media that exhibit sink
in development, when there is relatively little expe- conditions can be undertaken. Final selection of the
rience with the dissolution method, results are gen- actual medium for the test is based on empirical data
erally accepted at face value. However, as develop- using dissolution results from manufactured dosage
ment progresses, it is well recognized that issues with forms in the various candidate media. This process is
robustness and ruggedness are not uncommon. These enhanced when visual observations are made. When
may have profound effects, including additional test- appropriate for the phase of development, additional
ing and potential generation of out-of-specification data demonstrating robustness, ruggedness, and dis-
results. For these reasons, it is prudent to understand criminatory power can be used to refine the selection
the potential impact of variability as early in develop- of the medium.
ment as practical. This should include understand-
ing sensitivity of solubility or dissolution results
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Gregory P. Martin and Vivian A. Gray.

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