Salt Selection
Salt formation is a common and effective means of improving the bioavailability of poorly soluble acidic or basic drug compounds. The optimal salt form can improve the solubility and dissolution rate by several orders of magnitude over the parent. The screen and selection of a soluble salt form often provides a more convenient development pathway relative to amorphous solids, meta-stable polymorphs, and solid dispersions. Discovering a salt with adequate solubility can improve bioavailability, increase exposure and toxicological coverage, help reduce pharmacokinetic variations (dose-to-dose, inter-subject and inter-species), and enable simple formulations such as powder-in-bottle (PiB), powder-in-capsule (PiC), and suspensions to be used in preclinical and clinical studies in addition to commercial products.
Appropriate salt form selection:
The table below illustrates the increase in solubility by utilizing various salts forms:
Table II: Increasing Solubility via Salt Formation .
| API | Solubility (mg/mL) |
|---|---|
| CodeineFree-base Sulfate Phosphate |
8.3 33 445 |
| AtropineFree-base Sulfate |
1.1 2600 |
| PseudophedrineFree-base Hydrochloride |
0.2 2000 |
| CetirizineFree-base Di-hydrochloride |
0.03 300 |
Identifying a Salt that Enhances Bioavailability is also very critical as shown in the case study listed below.
Case study1:
Situation: Pharmacokinetic study in dogs indicated that solid doses of the free-base exhibited <1% F*
Target: Screen for a salt that will improve exposure
Action: Salt Screen (1 month)
- • 15 acids screened
- • Four hits identified
- • Detailed analyses highlighted tosylate salt as most viable (crystalline, non-solvated/hydrated, non-hygroscopic, stable)
Results
- • Solid-dose PK studies of tosylate salt in dogs exhibited 25% F
- • Tosylate salt selected for progression