Abstract
Salt formation is a well-established method to increase the solubility of ionizable drug candidates. However, possible conversion of salt to its original form of free acid or base—disproportionation—can have a drastic effect on the solubility and consequently the bioavailability of a drug. Therefore, during the salt selection process, the salt dissolution behavior should be well understood. Improved understanding could be achieved by a method that enables simultaneous screening of small sample amounts and detailed dissolution process analysis. Here, we use a machine-vision-based single-particle analysis (SPA) method to successfully determine the pH-solubility profile, intrinsic solubility, common-ion effect, pKa, pHmax, and Ksp values of three model compounds in a fast and low sample consumption (<1 mg) manner. Moreover, the SPA method enables, with a particle-scale resolution, in situ observation of the disproportionation process and its immediate effect on the morphology and solubility of dissolving species. In this study, a potentially higher energy thermodynamic solid-state form of diclofenac free acid and an intriguing conversion to liquid verapamil free base were observed upon disproportionation of the respective salts. As such, the SPA method offers a low sample consumption platform for fast yet elaborate characterization of the salt dissolution behavior.
Highlights
Salt formation is a well-established method to increase the solubility of ionizable drug candidates
The opposite relationship exists for basic drugs; a salt is formed below the pHmax, and a free base is in equilibrium with a solution above the pHmax.[10]
Naproxen free acid (NAP)−Na corresponds to the ASUBL Cambridge Structural Database (CSD) entry for the anhydrous salt form
Summary
Salt formation is a well-established method to increase the solubility of ionizable drug candidates. Salt formation is a well-established strategy used to increase the solubility of acidic and basic drugs.[1] The initial interest in salts dates back to studies on the dissolution rates of diverse salt forms by Nelson in the 1950s.2 This interest has been growing ever since, especially in recent decades, with the solubility of new chemical entities sharply decreasing due to production employing combinatorial chemistry and highthroughput screening.[3,4] potential salt form screening for a selected drug candidate is conducted in a high-throughput manner.[5,6] A rational continuation of the sequential process would be a high-throughput salt solubility or dissolution screen. If salt disproportionation occurs under gastrointestinal conditions, the potential enhancement of the dissolution rate and bioavailability can be lost
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