New conformational polymorph of hydrochlorothiazide with improved solubility.

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry

Background:

• Hydrochlorothiazide (HCT) is a widely used diuretic.
• Characterizing different polymorphic forms is crucial for drug development.
• Previous studies reported form I of HCT.

Purpose of the Study:

• To identify and characterize a new conformational polymorph of HCT.
• To compare the solubility of the new form with the existing commercial form.
• To establish the relationship between the new and previously reported HCT forms.

Main Methods:

• New HCT form (IA) synthesized via slow evaporation and solvent-antisolvent methods.
• Characterization using Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Spectroscopy (FTIR), Powder X-ray Diffraction (PXRD), and Single Crystal X-ray Diffraction (SCXRD).
• Equilibrium solubility studies conducted in water.

Main Results:

• DSC revealed a phase transition endotherm at 215.87°C, indicating a new polymorph.
• FTIR and PXRD confirmed the existence of the new polymorph (form IA).
• Single crystal studies showed distinct differences in bond and torsion angles between form IA and form I.
• Form IA demonstrated higher aqueous solubility (938 µg/mL) than form I (791 µg/mL).

Conclusions:

• Structural analysis, DSC, FTIR, and PXRD data confirm the existence of a new HCT conformer (form IA).
• The newly identified conformational polymorph (form IA) possesses significantly higher solubility.
• This finding is promising for the pre-formulation development of hydrochlorothiazide.