article, based on material from a 2003 PhRMA workshop on acceptable
analytical practices, provides guidance for developing dissolution
testing for poorly soluble compounds. The first article from
the workshop, about phased method validation, was published
in November, Future articles will cover analytical method
equivalency and justification of specifications.
Dissolution testing of poorly soluble compounds in immediate-release
(IR) solid dosage forms poses many challenges. These challenges
include developing and validating the test method, ensuring
that the method is appropriately discriminatory, and addressing
the potential for an in vivo-in vitro relationship (IVIVR)
or correlation (IVIVC). The objectives of dissolution testing,
in general, vary during the life cycle of a dosage form. The
primary objective during Phases 0 and I is to develop a method
to clearly establish the mechanism of in vitro drug release
and solubilization. During Phases II and III, the objective
shifts to identifying a test method that can provide an IVIVR,
IVIVC, or other biorelevant information. At registration and
beyond, the goal is to identify a quality control (QC) dissolution
test method to verify process and product consistency.
It is preferable to identify a dissolution test method that
can evaluate both product consistency and bioavailability.
This goal, however, remains a significant challenge for pharmaceutical
formulation and analytical scientists, and frequently is not
achievable. The literature, including regulatory positions,
provides little guidance about addressing these challenges
for poorly soluble compounds.
To collate acceptable practices and provide more guidance,
the Analytical Technical Group of the Pharmaceutical Research
and Manufacturers of America (PhRMA) included dissolution
testing of poorly soluble compounds in the PhRMA Acceptable
Analytical Practices Workshop held in September 2003 (1-2).
Representatives from PhRMA member companies met to discuss
the topic, share current practices, and agree on acceptable
practices that represent good science and meet current regulatory
requirements. The group also identified areas in which strategies
need to be developed. This article presents the output of
these discussions by providing a general overview of dissolution
testing and highlighting the relevant issues and test modifications
needed to test the dissolution of poorly soluble compounds.
Why in-vitro dissolution testing?
Characterizing the drug-release mechanism by establishing
an t in vitro dissolution test method (or an appropriate alternative
method) to measure product performance is particularly important
for poorly soluble compounds. Dissolution testing historically
has been a key tool during the development stages of a compound
as well as for commercial manufacturing. For a development
compound, dissolution testing is used primarily to help develop
and evaluate new formulations by evaluating the rate of drug
release from dosage forms, evaluating the stability of these
formulations, monitoring product consistency, assessing formulation
changes, and establishing IVIVRs of IVIVCs. For a commercial
product, dissolution testing is used primarily to confirm
manufacturing and product consistency, to evaluate the quality
of the product during its shelf life, and to assess postapproval
changes and the need for bioequivalency studies (3).
A dissolution test measures the rate of release of the drug.
The objective is to develop a discriminatory method that is
sensitive to variables that affect the dissolution rate. Such
variables may include characteristics of the active pharmaceutical
ingredient (API) (e.g., particle size, crystal form, bulk
density), drug product composition (e.g., drug loading, and
the identity, type, and levels of excipients), the drug product
manufacturing process (e.g., compression forces, equipment),
and the effects of stability storage conditions (e.g., temperature,
humidity). Although it also is desirable to develop a dissolution
test that establishes an IVIVC or an IVIVR, that kind of correlation
between observed changes in in vitro dissolution rate to meaningful
in vivo product performance quality remains a key challenge,
as will be explained below.
Classifying drugs according to dissolution and permeability
Mechanism of dissolution. The dissolution test determines
the cumulative amount of drug that goes into solution as a
function of time. As shown in Figure 1, dissolution of drug
from a dosage form involves at least two consecutive steps:
liberation of the solute or drug from the formulation matrix
(disintegration), followed by dissolution of the drug (solubilization
of the drug particles) in the liquid medium. The overall rate
of dissolution depends on the slower of these two steps. The
relative difference in rates should be carefully considered
when designing the dissolution method.
[FIGURE 1 OMITTED]
The cohesive properties of the formulated drug playa key
role in the first step of dissolution. For solid dosage forms,
these properties include disintegration and erosion, whereas
for semisolid or liquid formulations, the dispersion of lipids
or partitioning of the drug from the lipid phase is the key
factor. If the first step of dissolution is rate-limiting,
then the rate of dissolution is considered to be disintegration
controlled. Careful assessment of the intrinsic rate of dissolution
and the effect of various aspects of the formulation (e.g.,
release profiles from precompressed granules, impact of compression
force, porosity, and lubrication) can reveal the relative
contribution of the disintegration step to the overall dissolution
of the drug.
In the second step of dissolution--solubilization of the
drug particles--the physicochemical properties of the drug
such as its chemical form (e.g., salt, free acid, free base)
and physical form (e.g., amorphous or polymorph, and primary
particle size) play an important role. If this latter step
is rate limiting, then the rate of dissolution is intrinsic
dissolution controlled. This is the case for most poorly soluble
compounds in IR formulations. For poorly soluble compounds
in solubilized formulations, in vivo precipitation also may
need to be considered when developing a dissolution test method,
in particular for establishing an IVIVR or IVIVC.
The biopharmaceutics classification system (BCS) to define
poorly soluble compounds. In addition to classifying drugs
according to their disintegration and solubilization properties,
drugs also may be classified by additional factors such as
permeability. A classification system that uses permeability
is the biopharmaceutical classification system (BCS), which
is based on estimates of the contribution of solubility, permeability,
and dissolution to oral drug absorption from IR dosage forms.
First described in 1995, the BCS and its principles have been
used in several guidances issued by the Food and Drug Administration
BCS categories depend on a few key definitions, including
low-solubility, high permeability, and rapidly dissolving:
* Based on the BCS, low-solubility compounds are compounds
whose highest dose is not soluble in 250 mL or less of aqueous
media from pH 1.2 to 7.5 at 37 [degrees]C. For a low-solubility
compound, the highest dosage strength divided by the lowest
solubility in the pH range 1.2-7.5 would be greater than 250.
Solubility is primarily a property of the API and its salt
form. Solubility usually is determined by measuring the concentration
of a saturated solution after equilibration at 37 [degrees]C
for 1 to 24 h. The equilibration time depends on the test
duration time as well as the physical and chemical stability
(e.g., conversion of salt to free base in vitro) of the drug.
* High permeability is defined as human absorption of 90%
or more of the administered dose (6).
* A rapidly dissolving IR drug product is defined as one
for which no less than 85% of the label claim is dissolved
within 30 min, as tested using either USP Apparatus I at 100
rpm of USP Apparatus II at 50 rpm in pH 1.2 (0.1 N HCl or
simulated gastric fluid USP, without enzyme), pH 4.5 buffer,
and pH 6.8 buffer (or simulated intestinal fluid USP). (See
discussion below in "Apparatus selection.")
Using these definitions, drugs fall into one of four BCS
categories that describe the drug's permeability and absorption
properties as well as its dissolution.
Class I: High solubility, high permeability compounds.
Class II: Low-solubility, high-permeability compounds. For
these compounds, which are likely to demonstrate intrinsic
dissolution-limited absorption (i.e., the rate of drug solubilization
is much lower than the rate of drug absorption), it may be
possible to establish an IVIVR of IVIVC.