Crystal forms of a new 5-HT sub(4) receptor agonist DA-6886

DA-6886 is a new 5-HT sub(4) receptor agonist under development for the treatment of constipation-predominant irritable bowel syndrome. The objective of this work was to investigate the existence of polymorphs and pseudopolymorphs of DA-6886. Five crystal forms of DA-6886 have been isolated by recrystallization and characterized by differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, and powder X-ray diffractometry (PXRD). From the DSC and TG data, it was confirmed that Form 2 is \( {\raise0.5ex\hbox{$\scriptstyle 1$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) methanol solvate, Form 3 is 1 methanol solvate, Form 4 is \( 1{\raise0.5ex\hbox{$\scriptstyle 1$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) ethanol solvate, and Form 5 is \( 3{\raise0.5ex\hbox{$\scriptstyle 2$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) hydrate. The PXRD patterns of five crystal forms were different, respectively. In the dissolution studies in pH 6.8 plus or minus 0.05 buffer at 37 plus or minus 0.5 degree C, the solubility of Form 2 was the highest. And the dissolution rate at 5 min in water decreased in rank order: Form 2 > Form 4 > Form 1 > Form 3 > Form 5. After storage of 3 months at 2 degree C, 24 % relative humidity, Form 1, Form 2, Form 3, and Form 4 were not transformed, but Form 5 (\( 3{\raise0.5ex\hbox{$\scriptstyle 2$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) hydrate) was transformed to dihydrate.