Salt Selection in Drug Development - Pharmaceutical Technology

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Salt Selection in Drug Development
The selection of an appropriate salt form for a potential drug candidate is an opportunity to modulate its characteristics to improve bioavailability, stability, manufacturability, and patient compliance.

Pharmaceutical Technology
Volume 3, Issue 32

In spite of the numerous advantages associated with salt forms, developing them is not always feasible. The preparation of a stable salt may not be possible for some drugs. The salt may have certain undesirable properties compared with the free acid or base, and it would thus be appropriate to develop the free acid or base (28). In a salt-screening study of RPR111423, a pyridine base, hydrochloride and mesylate salts were formed. The hydrochloride salt showed a loss of hydrogen chloride at high temperatures (110–120 C) and precipitation at an acidic pH because of the common-ion effect. The mesylate salt also showed precipitation at acidic pH. The two salts were polymorphic and hygroscopic in comparison with free base, which was nonpolymorphic and nonhygroscopic. These results proved the free base to be a better candidate than the salt forms (29).

Pharmacological indications also help determine whether the salt form or the free acid or base should be pursued. For example, when a slow onset or a constant plasma level is required, a highly ionized salt form may be inappropriate if the free acid or base provides a sufficient plasma level. Tolbutamide sodium, an antihyperglycemic agent, causes a rapid fall in blood glucose levels because it is highly ionized. This characteristic causes hypoglycemia in patients with normal insulinomas. Therefore, tolbutamide sodium's corresponding free acid was preferred for oral administration. The salt form's only application is the diagnosis of pancreatic adenomas (30).

Table II: The selection of potential salt forms based on intended pharmaceutical profile.
Pharmaceutical considerations. The choice of salt is governed largely by the acidity or basicity of the ionizable group, the safety of the counterion, the drug indications, the route of administration, and the intended dosage form. The expectations of the salt form must be outlined as a desirable pharmaceutical profile that guides the synthesis of the salt forms (see Table II).

Ionic considerations. The degree of ionization is a critical parameter for the physiological performance of the drug and for its formulation development (25). The pK a of the drug and counterion is important for successful salt formation as well. For the preparation of salt forms of basic drugs, the pK a of the counterion should be at least 2 pH lower than the pK a of the drug (34). Similarly, for the preparation of salt forms of acidic drugs, the pK a of the counterion should be at least 2 pH higher than the pK a of the drug. These specifications are required because the counterion must bring the solution's pH to a level lower than the pHmax (see Figure 2) to reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base (5). The generalized rule of difference in pK a units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pK a of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment (35).


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