After crystallinity assessment, the salt form's hygroscopicity profile is assessed to find a salt form that retains its properties
in the varying humidity conditions of pharmaceutical operations. This assessment can be performed using methods such as traditional
saturated salt solutions in a desiccator or more advanced dynamic vapor sorption methods. The salt forms with acceptable hygroscopicity
profiles are then evaluated for their solubility. The salts with adequate solubility are tested for their physicochemical
stability, including polymorphic stability and excipient compatibility. These tests are especially relevant in combination
formulations such as aspirin–propoxyphene. Aspirin–propoxyphene hydrochloride is unstable, but aspirin–propoxyphene napsylate
is stable (8).
Salt forms having adequate stability are assessed for variability in their properties resulting from polymorphism. Compounds
with a limited number of polymorphs are preferred because their performance during pharmaceutical operations and performance
is predictable. The salt forms that qualify the stage of polymorphism are tested for process control, economic feasibility,
and processability (including parameters such as corrosiveness, taste, wettability, and flowability). These criteria are generally
evaluated at a small scale by a medicinal chemist, who narrows the choice to a particular salt form. However, after a particular
salt form is selected, these parameters are evaluated at a larger scale so that the selected salt form has properties that
are easily controlled batchwise and over time.
The selected salt form is subjected to pharmacological testing for drug release as per the requirements of onset and the duration
of activity. Pharmacological safety studies are also performed. For example, epinephrine borate causes occasional mild stinging
in the eye, compared with hydrochloride and bitartrate salt, which cause moderate to severe stinging (44). The selected salt
form may then be subjected to extensive long-term toxicology studies in Phase I clinical trials of drug development.
Patent aspects of salt forms
Salt-selection studies provide a viable extension of a drug's patent because salts with superior properties can be patent-protected.
New salt forms often have novel physical properties related to processability (e.g., crystallization, morphology, and filtration)
and formulation (e.g., stability) (45). They may also result in the detection of new polymorphs (1).
A new salt form may have a profile that makes it suitable for a new route of administration. For example, diclofenac sodium
salt (Ciba-Geigy) was marketed as Voltaren. Before the Voltaren patent expired, other salts (e.g., diclofenac diethylamine)
with substantially better skin-penetration properties were discovered and patented. These salts, in corresponding formulations,
were particularly suitable for topical applications. Patenting new salts, therefore secures an exclusive position in the market
Selecting an appropriate salt form of an API may also play a role in blocking the development of generic drug products. Dr.
Reddy's Laboratories tried to obtain marketing authorization for amlodipine maleate, a different salt version of amlodipine
besylate. However, the US Court of Appeals for the Federal Circuit concluded that the basic patent for amlodipine covers other
salt forms of the drug, including its maleate salt. The verdict against Dr. Reddy's Laboratories effectively prevented the
generic version from entering the market (19).
Regulatory aspects of salt forms
Salt-selection studies should consider the regulatory aspects of introducing a new salt form. A new salt form of an approved
drug substance is considered a new chemical entity, thus requiring a full dossier to be submitted for marketing approval (1).
For regulatory purposes, a new salt form is designated a "pharmaceutical alternative" to the original form (46, 47). However,
the approval process for a new salt may use some of the details already known about the active entity of a related, previously
accepted salt (1). Therefore, when scientists change the active moiety of a salt that is already marketed, they may usually
submit an abbreviated application, popularly known as the 505 b(2) filings (or the hybrid NDA), if they can prove that the
new salt form's active moiety has the same pharmacokinetics, pharmacodynamic, and toxicity characteristics as the original
(19). A generic version of a drug based on an alternative salt form may also be approved in a similar way. However, the benefits
expected from the introduction of a new salt form must be weighed against the cost and time involved in the studies required
for regulatory approval.