In situ salt screening--a useful technique for discovery support and preformulation studies

Area of Science:

• Pharmaceutical Chemistry
• Drug Development
• Solid-State Chemistry

Background:

• Salt formation is crucial for optimizing drug properties like solubility and bioavailability.
• Traditional salt screening methods can be time-consuming and resource-intensive.
• GW1818, an alpha 1A adrenergic receptor antagonist, is a potential treatment for benign prostatic hyperplasia (BPH).

Purpose of the Study:

• To introduce and validate a novel in situ salt screening technique for basic pharmaceutical compounds.
• To demonstrate the applicability of this technique using GW1818 as a model compound.
• To assess the technique's efficiency in identifying suitable pharmaceutical salts for formulation.

Main Methods:

• The in situ salt screening involved acid selection, solubility studies, residual solid characterization, and Ksp/solubility calculations.
• Six acids were screened for salt formation with GW1818.
• Solid-state properties were analyzed using microscopy, differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD).

Main Results:

• The in situ technique showed excellent agreement with traditional salt screening solubility results.
• Four crystalline salts (phosphate, succinate, mesylate, hydrochloride) of GW1818 exhibited adequate solubility and were selected for further evaluation.
• Citrate and tartrate salts showed solubility but were difficult to crystallize, serving as backup candidates.

Conclusions:

• The in situ salt screening technique is a time- and compound-conserving method for prioritizing salt selection.
• This technique provides valuable solubility and stability data for formulation development in research and development.
• The method facilitates the development of formulations, such as an IV formulation for GW1818, for preclinical studies.