Toxicology formulation selection
The earliest drug-product formulation is often developed for toxicological studies in animals where repeated dose toxicity
studies are conducted before human Phase I clinical trials. The aim of the toxicity study is to obtain sufficient exposure
of the animal to the drug substance and its metabolites.
In general, formulations at this stage of development should be simple, consisting of, for example, a solution, suspension,
or API in a capsule. Typical studies include pharmacokinetic (PK) research of salt versus base, solution versus suspension,
a comparison of various salts, and an assessment of dose linearity. For the toxicological study, the high dose is selected
to enable identification of the target organ toxicity; the systemic exposure achieved should be a significant multiple of
the anticipated clinical systemic exposure. Biopharmaceutics Classification System (BCS) Class II and IV compounds with extremely
low solubility often have limited or less than dose proportional exposure at high doses (3). Small-volume or even large-volume
dissolution testing serves as a valuable tool for toxicology formulation selection. Common formulation approaches include
the use of different salt forms; addition of surfactant, cosolvent, or lipid vehicle; or use of amorphous API with crystallization
inhibitor. Dissolution should be conducted with media at a gastrointestinal pH relevant to the animal species. Animal studies
with these early formulations provide an important opportunity to understand the in vivo behavior of the drug substance and provide early insight into formulation development choices.
The dissolution data can supplement the animal PK data as well. For instance, highly variable animal PK data with less variable
dissolution data may indicate a metabolic or physiological cause. In the absence of dissolution data, one may suspect physicochemical
properties such as uneven distribution of drug in the formulation or aggregation to be the cause.
Phase I formulation development
Salt selection, excipient compatibility, and formulation concepts for the first administration of a drug to humans are studied
during Phase I. Dissolution serves as a useful tool in the variant selection process and in the stability assessment of the
formulation. During this phase, however, every attempt must be made to lay a foundation for QbD principles, IVIVC, and IVIVR.
The BCS classification of the drug should be established and serve as a guide for the selection of an appropriate dissolution
test or surrogate test(s). A surrogate test can supplement dissolution data and potentially replace dissolution testing after
enough developmental data are collected that demonstrate the surrogate test to be an equally good or better indicator of product
If an extended-release formulation is the objective for a BCS I or BCS III compound, IVIVC should be attempted for different
dissolution-rate formulations and in vivo data. For immediate-release (IR) formulations, initial dissolution testing should be performed in SGF, simulated intestinal
fluid (SIF), and in pH 1.2, 4.5, and 6.8 buffers. If the amount of drug released is greater than 85% in 15 min and the stability
of the formulation is favorable under stressed storage conditions, disintegration should be used as the test method of choice
For BCS II and IV compounds, initial dissolution should be performed in media of different pH. Addition of surfactants and
use of biorelevant dissolution media may also be considered. For acidic drugs, dissolution may be performed in pH 4.5–7.5
buffers with surfactants, if necessary, to choose an appropriate medium. For basic drugs or salts, the dissolution may be
performed in pH 1–2 buffers with surfactants, if necessary. A two-step dissolution may be performed to determine if and at
what rate the base precipitates at higher pH medium (5). In this case, a slower precipitation rate is preferred as it may
provide enough of a window for absorption to occur.
Value of dissolution testing: Phase II clinical development
During Phase I of clinical development, sufficient information about the pharmacokinetics of an investigational drug is obtained
to permit the design of scientifically valid Phase II studies. The dosage form and its unique specifications are, in most
cases, not finalized in early Phase II studies. One of the aims of Phase II studies, however, is to define the dosage form
that will be tested in Phase III studies. At this stage of development, a dissolution test can be used to:
- Develop the formulation and process
- Elucidate the drug-release mechanism
- Demonstrate a link between design space and the target product profile
- Monitor collective changes in the dosage form's stability testing
- Control quality of batch release and batch-to-batch consistency.