The stage of salt selection in drug development. Pharmaceutical companies previously selected salts at various stages in drug development. However, companies now tend to
move the salt-selection process to the research phase to make the process more foolproof (25). Ideally, the salt form should
be chosen before long-term toxicology studies are performed (i.e., at the start of Phase I clinical trials) (24). This timing
is an important factor in the early stages of new-drug development because changing the salt form at a later stage may force
a repetition of toxicological, formulation, and stability studies, thus increasing development time and cost (26). A new salt
form introduced at a late stage must also be evaluated for potential impurity changes, and its bioequivalence (bio-bridge),
pharmacokinetic equivalence (PK-bridge), and toxicity equivalence (tox-bridge) to the previous salt form must be proven.
Objectives of salt selection.
Innumerable salt forms are available to pharmaceutical scientists. The selection process must therefore be rational and streamlined.
A lack of proper planning may lead to the synthesis of several salt forms of the drug candidate for preformulation testing.
Moreover, this hit-or-miss approach results in many failures and may cause the loss of test substance and time. These considerations
underscore the need for a well-formatted decision tree to help scientists choose a suitable salt form in an efficient and
timely manner, depending upon the intended use, with a minimum number of failures and expended resources.
The main objective of a salt-selection study is to identify the salt form most suitable for development. The following four
parameters are often considered primary or essential criteria for the selection of a particular form:
- Aqueous solubility measured at various pH values, depending upon the intended pharmaceutical profile
- High degree of crystallinity
- Low hygroscopicity (i.e., water absorption versus relative humidity), which gives consistent performance
- Optimal chemical and solid-state stability under accelerated conditions (i.e., minimal chemical degradation or solid-state
changes when stored at 40 °C and 75% relative humidity).
A serious deficiency in any of these characteristics should exclude that form from further development. In addition to these
essential criteria, the following desirable criteria also influence salt-form selection:
- Limited number of polymorphs or absence of variability because of polymorphism
- Ease of synthesis, handling, or formulation development (27).
A single salt form generally cannot satisfy all the requirements for developing drug-substance dosage forms. However, introducing
a second or third salt form consumes additional developmental resources and increases the cost of manufacturing, handling,
storing, and characterizing the additional salt forms. Therefore, the dosage form is developed with a single salt form whenever
possible (9). The major drug-development issues are addressed by choosing the appropriate salt form. Minor issues can be addressed
using other development tools. Decreasing development timelines intensify the pressure to select the right salt form the first
time. Salt selection is a critical step in the preformulation stage of drug development. Gould says that "the balance required
in assessing the correct salt from to progress into drug development makes it a difficult semiempirical exercise" (8). This
statement emphasizes the need to prioritize the salt-selection process so that various development issues are addressed as
early as possible.
Potential candidate for salt formation.
The decision about whether salt or free acid or base should be developed depends on these forms' relative pharmaceutical
and commercial merits. If the active compound is a liquid, a solid dosage form is usually preferred because oil is difficult
to purify, characterize, and maintain in its effective form. Oil is also difficult to transport, sensitive to oxygen, and
susceptible to batch-to-batch variations. If the free acid or base is a water-soluble solid with a high melting point, preparing
a salt form is generally unnecessary. Alternatively, several useful properties of salt forms may be explored (6).