Solid form selection of zwitterionic 5-HT4 receptor agonist.
From discovery synthesis of a zwitterionic pharmaceutical compound, 4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-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 degrees 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.
Kojima
Takashi
T
Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc., Aichi 470-2393, Japan. tak_kojimajpn@yahoo.co.jp
Sugano
Kiyohiko
K
Onoue
Satomi
S
Murase
Noriaki
N
Sato
Morimichi
M
Kawabata
Yohei
Y
Mano
Takashi
T
D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D006813:Humidity; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry*; D014961:X-Ray Diffraction
D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists