Polymorphic forms of (5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione hydrobromide (02-Feb-2010)

      Polymorphic forms of (5-((4-(2-(methyl-2- pyridinylamino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione hydrobromide

(5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione is an anti-diabetic drug from the thiazolidinedione class which acts primarily by increasing insulin sensitivity. This molecule has the following structure:

N N O NH

S

O

Provided are crystalline form of (5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione hydrobromide: Form I, Form III, and Form IV.

Form I is characterized by a powder XRD pattern having peaks at about 15.2, 17.8,
22.9 and 24.5 ± 0.2 degrees two-theta.

Form III is characterized by a powder XRD pattern having peaks at about 4.5, 10.9,
17.0, 18.3, and 19.1 ± 0.2 degrees two-theta. It can also be characterized by a powder XRD pattern with three peaks at about 10.9, 18.3 and 19.1 ± 0.2 degrees two-theta and two peaks selected from the list of five peaks at about 4.5, 14.4, 16.3, 17.0 and
17.9 ± 0.2 degrees two-theta. Alternatively, Form III can be characterized by a powder XRD pattern with peaks at about 4.5, 10.9 and 19.1 ± 0.2 degrees two-theta and additional peaks at about 16.3, 14.4, 17.0 and 17.9 ± 0.2 degrees two-theta.

Form IV is characterized by a powder XRD pattern having peaks at about 5.4, 9.1,
10.7, 15.0, and 18.3 ± 0.2 degrees two-theta. Form IV can be also characterized by a powder XRD pattern with five peaks at about 5.4, 9.1, 10.7, 15.0 and 18.3 ± 0.2 degrees two-theta and additional four peaks at about 7.8, 14.8, 20.0 and 29.0 ± 0.2 degrees two-theta.

Example 1: Process for the preparation of Form III:

A 1000 ml flask was charged with (5-((4-(2-(methyl-2- pyridinylamino)ethoxy)phenyl) methyl)-2,4-thiazolidinedione (50 g) and demineralized water (500 ml). The suspension was heated to reflux and then aqueous Hydrobromic acid 47-48% was added (20 ml) drop wise to obtain a clear solution,

1

O

stirred for an additional 30-45 minutes and cooled to room temperature while stirring for 19-20 hours. The resulting solid was filtered under reduced pressure and washed by demineralized water (50 ml). Finally dried at 48-50^oC under reduced pressure to give 52 g (85%) of a white solid. The resulting solid was analyzed by XRD to yield Form III.

Example 2: Process for the preparation of Form IV:
150mg of (5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl) methyl)-2,4- thiazolidinedione HBr Form I was placed into plastic cup of 100 ml volume and wetted by 1 ml of analytical acetone. The cup was then closed by its cover and placed in water bath that was heated to 30°C for 24 hrs. The resulting solid was analyzed by PXRD and showed Form IV.

Example...