Solid form selection of zwitterionic 5-HT4 receptor agonist

Abstract

From discovery synthesis of a zwitterionic pharmaceutical compound, 4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2 H-pyran-4-carboxylic acid (compound A), two anhydrous ZW-I and ZW-II and two hydrate forms ZW-III and ZW-IV were identified. Although stable form ZW-I was chemically stable at 70 °C/75% RH for 10 days, it was transformed to hydrate form ZW-IV under ambient conditions within a few days, taking up water from atmospheric moisture. In order to select a solid form for further investigation, solid-state characterization, salt screening on 96-well plate, stable polymorph and hydrate screening and physical stability were performed. Based on the results of the salt screening, besylate, camsylate, hemi-edisylate, hemifumarate, monosuccinate salts of compound A were prepared, and their polymorphism and chemical and physical stability were evaluated. From the viewpoint of stability and manufacturability, a stable form of besylate salt (BSA-I), which had two anhydrous forms BSA-I and BSA-II and hydrate form BSA-III, was selected as a solid form. BSA-I was quite stable at high relative humidity and provided significant improvement of physical stability compared with ZW-I.