Solid form selection of zwitterionic 5-HT4 receptor agonist

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry

Background:

• Discovery synthesis of zwitterionic compound A yielded multiple solid forms (ZW-I, ZW-II, ZW-III, ZW-IV).
• The initially stable ZW-I form degraded to a hydrate (ZW-IV) under ambient conditions due to moisture uptake.

Purpose of the Study:

• To select an optimal solid form of compound A for further development.
• To evaluate the stability and manufacturability of various salt forms.

Main Methods:

• Solid-state characterization of compound A and its salts.
• Salt screening using a 96-well plate format.
• Polymorph and hydrate screening.
• Chemical and physical stability assessments under various conditions.

Main Results:

• Multiple anhydrous and hydrate forms of compound A were identified.
• Besylate, camsylate, hemi-edisylate, hemifumarate, and monosuccinate salts were prepared and evaluated.
• The besylate salt form (BSA-I) exhibited excellent chemical and physical stability, particularly at high relative humidity, outperforming ZW-I.

Conclusions:

• The besylate salt form (BSA-I) was selected as the most promising solid form for compound A due to its enhanced stability and manufacturability.
• BSA-I offers significant improvements in physical stability compared to the ZW-I form.